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Kaur G, Tiwari P, Singla S, Panghal A, Jena G. The intervention of NLRP3 inflammasome inhibitor: oridonin against azoxymethane and dextran sulfate sodium-induced colitis-associated colorectal cancer in male BALB/c mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03871-z. [PMID: 40035821 DOI: 10.1007/s00210-025-03871-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/31/2025] [Indexed: 03/06/2025]
Abstract
Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance.
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Affiliation(s)
- Gurpreet Kaur
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Priyanka Tiwari
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Shivani Singla
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Archna Panghal
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Gopabandhu Jena
- Facility of Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India.
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Xie Y, Liu F, Wu Y, Zhu Y, Jiang Y, Wu Q, Dong Z, Liu K. Inflammation in cancer: therapeutic opportunities from new insights. Mol Cancer 2025; 24:51. [PMID: 39994787 PMCID: PMC11849313 DOI: 10.1186/s12943-025-02243-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025] Open
Abstract
As one part of the innate immune response to external stimuli, chronic inflammation increases the risk of various cancers, and tumor-promoting inflammation is considered one of the enabling characteristics of cancer development. Recently, there has been growing evidence on the role of anti-inflammation therapy in cancer prevention and treatment. And researchers have already achieved several noteworthy outcomes. In the review, we explored the underlying mechanisms by which inflammation affects the occurrence and development of cancer. The pro- or anti-tumor effects of these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, and extracellular matrix are discussed. Since FDA-approved anti-inflammation drugs like aspirin show obvious anti-tumor effects, these drugs have unique advantages due to their relatively fewer side effects with long-term use compared to chemotherapy drugs. The characteristics make them promising candidates for cancer chemoprevention. Overall, this review discusses the role of these inflammatory molecules in carcinogenesis of cancer and new inflammation molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that have already been or are expected to be applied in clinical practice, as well as recent discoveries of the anti-tumor effect of non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. The advantages and disadvantages of their application in cancer chemoprevention are also discussed.
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Affiliation(s)
- Yifei Xie
- Department of Pathology and Forensic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Fangfang Liu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Yunfei Wu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yuer Zhu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Yanan Jiang
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Qiong Wu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China
| | - Zigang Dong
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China.
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China.
| | - Kangdong Liu
- State Key Laboratory of Metabolic Dysregulation & the Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan, 450052, China.
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450007, China.
- The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450001, China.
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Alqudah A, Qnais E, Gammoh O, Bseiso Y, Wedyan M, Oqal M. Panduratin A mitigates inflammation and oxidative stress in DSS-induced colitis mice model. Future Sci OA 2024; 10:2428129. [PMID: 39559852 PMCID: PMC11581177 DOI: 10.1080/20565623.2024.2428129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 10/14/2024] [Indexed: 11/20/2024] Open
Abstract
AIM This study explored Panduratin A's protective effects against DSS-induced colitis in mice, focusing on reducing inflammation and oxidative stress in the colon. METHODS Mice were treated with dextran sodium sulfate (DSS) and Panduratin A (3, 6, 18 mg/kg), and changes in body weight, colon length, Disease Activity Index (DAI), histopathology, inflammation markers including tumor necrosis factor- α (TNF-α), Interleukin-1 β (IL-1β), Myeloperoxidase (MPO), and oxidative stress, Malondialdehyde (MDA) were evaluated. RESULTS Panduratin A significantly reversed DSS-induced symptoms, including body weight loss, colonic length shortening, and DAI increase, while reducing histopathological damage. It lowered inflammatory markers and oxidative stress, suppressed NF-κB activation, and enhanced Nrf2 and HO-1 expression. CONCLUSION Panduratin A shows promise as a colitis treatment, warranting further research for broader clinical application.
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Affiliation(s)
- Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
| | - Esam Qnais
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Yousra Bseiso
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammed Wedyan
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Muna Oqal
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
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DeLira-Bustillos N, Angulo-Zamudio UA, Leon-Sicairos N, Flores-Villaseñor H, Velazquez-Roman J, Tapia-Pastrana G, Canizales-Quinteros S, Velázquez-Cruz R, Cortez-Hernández JA, Canizalez-Roman A. Cyclomodulins-harboring Escherichia coli isolated from obese and normal-weight subjects induces intestinal dysplasia in a mouse model. World J Microbiol Biotechnol 2024; 40:371. [PMID: 39487241 DOI: 10.1007/s11274-024-04176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024]
Abstract
Recently, cyclomodulins have been identified in Escherichia coli (E. coli), which can induce dysplastic damage. This work aimed to determine the dysplastic activity of cyclomodulin-harboring E. coli isolated from CRC patients, obese and normal-weight subjects in a mouse model. Forty-two mice were pretreated with streptomycin, azoxymethane, and dextran sodium sulfate. Mice were infected with E. coli pks + isolated from a CRC patient, with E. coli pks + cif + isolated from obese or normal-weight subjects, or with E. coli HB101. The presence of cyclomodulin-harboring E. coli in the feces, weight loss, changes in fecal consistency, and the presence of blood in the feces were monitored and used to assess the disease activity index (DAI). After 62 days, the mice were sacrificed to evaluate the presence of intestinal polyps and dysplastic damage by histologic sections. Cyclomodulin-harboring E. coli colonized the mice; these mice exhibited weight loss and watery diarrhea, and isolated normal-weight E. coli had a higher DAI. Polyps were observed in mice infected with cyclomodulin-harboring E. coli in the ileum but to a greater extent in obese isolates. E. coli isolated from CRC showed more significant endothelial damage associated with dysplasia in the ileum in equal proportions from obese and normal-weight isolates. In conclusion, E. coli harboring cyclomodulins isolated from CRC, obesity, or normal weight can cause dysplastic damage in the ileum of mice and may be a risk factor for CRC development.
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Affiliation(s)
- Nora DeLira-Bustillos
- Programa de Doctorado, Posgrado Integral en Biotecnología, FCQB, UAS, Culiacan Sinaloa, 80030, Mexico
| | | | - Nidia Leon-Sicairos
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
- Pediatric Hospital of Sinaloa, Culiacan Sinaloa, 80200, Mexico
| | - Hector Flores-Villaseñor
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
- The Sinaloa State Public Health Laboratory, Secretariat of Health, Culiacan Sinaloa, 80058, Mexico
| | - Jorge Velazquez-Roman
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico
| | - Gabriela Tapia-Pastrana
- Laboratorio de Investigación Biomédica, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS- BIENESTAR) Hospital Regional de Alta Especialidad de Oaxaca, Oaxaca, 71256, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/INMEGEN, Mexico City, 14610, Mexico
| | - Rafael Velázquez-Cruz
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico
| | | | - Adrian Canizalez-Roman
- School of Medicine, Autonomous University of Sinaloa, Culiacan, Sinaloa, 80019, Mexico.
- The Women's Hospital, Secretariat of Health, Culiacan Sinaloa, 80020, Mexico.
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Hachiya K, Masuya M, Kuroda N, Yoneda M, Nishimura K, Shiotani T, Tawara I, Katayama N. Pravastatin prevents colitis-associated carcinogenesis by reducing CX3CR1 high M2-like fibrocyte counts in the inflamed colon. Sci Rep 2024; 14:23021. [PMID: 39362935 PMCID: PMC11449942 DOI: 10.1038/s41598-024-74215-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024] Open
Abstract
Colorectal cancer (CRC) resulting from chronic inflammation is a crucial issue in patients with inflammatory bowel disease (IBD). Although many reports established that intestinal resident CX3CR1high macrophages play an essential role in suppressing intestinal inflammation, their function in colitis-related CRC remains unclear. In this study, we found that colonic CX3CR1high macrophages, which were positive for MHC-II, F4/80 and CD319, promoted colitis-associated CRC. They highly expressed Col1a1, Tgfb, II10, and II4, and were considered to be fibrocytes with an immunosuppressive M2-like phenotype. CX3CR1 deficiency led to reductions in the absolute numbers of CX3CR1high fibrocytes through increased apoptosis, thereby preventing the development of colitis-associated CRC. We next focused statins as drugs targeting CX3CR1high fibrocytes. Statins have been actively discussed for patients with IBD and reported to suppress the CX3CL1/CX3CR1 axis. Statin treatment after azoxymethane/dextran sulfate sodium-induced inflammation reduced CX3CR1high fibrocyte counts and suppressed colitis-associated CRC. Therefore, CX3CR1high fibrocytes represent a potential target for carcinogenesis-preventing therapy, and statins could be safe therapeutic candidates for IBD.
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Affiliation(s)
- Kensuke Hachiya
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan
| | - Masahiro Masuya
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan.
- Course of Nursing Science, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan.
| | - Naoki Kuroda
- Department of Gastroenterology, Saiseikai Matsusaka General Hospital, Matsusaka, 515- 8557, Mie, Japan
| | - Misao Yoneda
- Department of Clinical Nutrition Medical Technology Course, Suzuka University of Medical Science, Suzuka, 510-0293, Mie, Japan
| | - Komei Nishimura
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Takuya Shiotani
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
| | - Naoyuki Katayama
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, 514-8507, Mie, Japan
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Li Q, Zhang S, Zhou Q, Gu C, Liu Y, Zhang J, Zhang J. Tocotrienol suppresses colitis-associated cancer progression through TLR4 signaling in a mouse model of colorectal cancer. Curr Res Toxicol 2024; 7:100196. [PMID: 39411685 PMCID: PMC11474223 DOI: 10.1016/j.crtox.2024.100196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 09/20/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
This study aimed to evaluate the preventive efficacy of tocotrienol in inhibiting the nuclear factor-kappa B (NF-κB) mediated inflammation pathways in colorectal cancer. We utilized the azoxymethane (AOM) and dextran sulfate sodium salt (DSS) to induce colitis-associated colorectal cancer (CAC) mice model. In generating a CAC model, mice were intraperitoneally injected with AOM at a concentration of 10 mg/kg body weight. Seven days after the AOM injection, mice drinking water containing 3 % DSS for 1 week, followed by a 2-week period of regular water. This cycle of DSS treatment (1-week 3 % DSS+2-week water) was repeated for two additional cycles. Mice were randomly divided into five groups (n = 20/group), including Blank group, Model group, three different dosages tocotrienol groups (Low dose group [50 mg/kg], Medium dose group [75 mg/kg], and High dose group [100 mg/kg]). The protective effects of tocotrienol were assessed using histological, flow cytometry, western blot and mouse Luminex assay. Compared with the blank group, expressions of toll-like receptor 4 (TLR4), myeloid differentiation protein 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6), NF-κB, Interleukin (IL)-6 and tumor necrosis factor (TNF) -α were increased in model group, while IL-4 and IL-10 were decreased in model group (P<0.05). Tocotrienol prevented carcinogenesis and decreased the IL-6, TNF-α, MyD88, TLR4, TRAF-6 and NF-κB expression levels, compared with the model group (P<0.05). Compared with the model group, the expression of IL-10 was increased in medium dose group and high dose group (P<0.05). The protective effects of tocotrienol may be related to the inhibition of TLR4 /MyD88 /NF-κB mediated inflammatory signaling pathways. Therefore, the use of tocotrienol can improve the abnormal expression of cytokines in a mouse model of colorectal cancer and inhibit the occurrence and development of colorectal cancer.
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Affiliation(s)
- Qian Li
- School of Public Health, Qilu Medical University, Shandong 255300, China
| | - Shujing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Qinghong Zhou
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Chenxi Gu
- Disease Prevention and Control Center of Binhu District, Wuxi City, Jiangsu 214100, China
| | - Yinghua Liu
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Jing Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
- NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Tianjin 300011, China
| | - Jingshu Zhang
- School of Public Health, Nanjing Medical University, Nanjing 211166, China
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Tian H, Ge K, Wang L, Gao P, Chen A, Wang F, Guo F, Wang F, Zhang Q. Advances in PGD2/PTGDR2 signaling pathway in tumors: A review. BIOMOLECULES & BIOMEDICINE 2024; 24:1055-1067. [PMID: 38704736 PMCID: PMC11378995 DOI: 10.17305/bb.2024.10485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 05/07/2024]
Abstract
Studies have shown that the prostaglandin (PG) family acts as an allergic inflammatory mediator in malignant diseases. Furthermore, prostaglandin E2 (PGE2) and its related receptors, as well as the prostaglandin D2 (PGD2)/PGD2 receptor (PTGDR2), play irreplaceable roles in tumorigenesis and anti-tumor therapy. Several experiments have demonstrated that PGD2 signaling through PTGDR2 not only directly inhibits cancer cell survival, proliferation, and migration but also reduces resistance toward conventional chemotherapeutic agents. Recent studies from our and other laboratories have shown that PGD2, its ligands, and related metabolites can significantly alter the tumor microenvironment (TME) by promoting the secretion of chemokines and cytokines, thereby inhibiting tumor progression. Additionally, reduced PGD2 expression has been associated with poor prognosis in patients with gastric, breast, lung, and pancreatic cancers, validating the preclinical findings and their clinical relevance. This review focuses on the current understanding of PGD2/PTGDR2 expression patterns and biological activity in cancer, proposing questions to guide the assessment of PGD2 and its receptors as potential targets for effective cancer therapies.
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Affiliation(s)
- Hengjin Tian
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
- Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, China
| | - Kunpeng Ge
- Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, China
| | - Lulu Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Peiyao Gao
- Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, China
| | - Amin Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Feifan Wang
- Department of Blood Transfusion, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Fangzheng Guo
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
| | - FengChao Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Qiang Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
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Li Q, Liu Y, Li B, Zheng C, Yu B, Niu K, Qiao Y. Bioinformatics analysis of oxidative stress genes in the pathogenesis of ulcerative colitis based on a competing endogenous RNA regulatory network. PeerJ 2024; 12:e17213. [PMID: 39161963 PMCID: PMC11332386 DOI: 10.7717/peerj.17213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 03/19/2024] [Indexed: 08/21/2024] Open
Abstract
Background Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic.
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MESH Headings
- Animals
- Humans
- Mice
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/chemically induced
- Computational Biology
- Databases, Genetic
- Dextran Sulfate/toxicity
- Disease Models, Animal
- Gene Expression Profiling
- Gene Regulatory Networks/drug effects
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Oxidative Stress/genetics
- Oxidative Stress/drug effects
- RNA, Competitive Endogenous/genetics
- RNA, Competitive Endogenous/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
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Affiliation(s)
- Qifang Li
- Department of Traditional Chinese Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yuan Liu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Bingbing Li
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Canlei Zheng
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Bin Yu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Kai Niu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Yi Qiao
- School of Public Health, Jining Medical University, Jining, Shandong, China
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Fan Y, Meng Y, Hu X, Liu J, Qin X. Uncovering novel mechanisms of chitinase-3-like protein 1 in driving inflammation-associated cancers. Cancer Cell Int 2024; 24:268. [PMID: 39068486 PMCID: PMC11282867 DOI: 10.1186/s12935-024-03425-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 07/01/2024] [Indexed: 07/30/2024] Open
Abstract
Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is induced and regulated by multiple factors during inflammation in enteritis, pneumonia, asthma, arthritis, and other diseases. It is associated with the deterioration of the inflammatory environment in tissues with chronic inflammation caused by microbial infection or autoimmune diseases. The expression of CHI3L1 expression is upregulated in several malignant tumors, underscoring the crucial role of chronic inflammation in the initiation and progression of cancer. While the precise mechanism connecting inflammation and cancer is unclear, the involvement of CHI3L1 is involved in chronic inflammation, suggesting its role as a contributing factor to in the link between inflammation and cancer. CHI3L1 can aggravate DNA oxidative damage, induce the cancerous phenotype, promote the development of a tumor inflammatory environment and angiogenesis, inhibit immune cells, and promote cancer cell growth, invasion, and migration. Furthermore, it participates in the initiation of cancer progression and metastasis by binding with transmembrane receptors to mediate intracellular signal transduction. Based on the current research on CHI3L1, we explore introduce the receptors that interact with CHI3L1 along with the signaling pathways that may be triggered during chronic inflammation to enhance tumorigenesis and progression. In the last section of the article, we provide a brief overview of anti-inflammatory therapies that target CHI3L1.
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Affiliation(s)
- Yan Fan
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Yuan Meng
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Xingwei Hu
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China.
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China.
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10
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Wang Z, Chang Y, Sun H, Li Y, Tang T. Advances in molecular mechanisms of inflammatory bowel disease‑associated colorectal cancer (Review). Oncol Lett 2024; 27:257. [PMID: 38646499 PMCID: PMC11027113 DOI: 10.3892/ol.2024.14390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 03/15/2024] [Indexed: 04/23/2024] Open
Abstract
The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.
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Affiliation(s)
- Zhi Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yu Chang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haibo Sun
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yuqin Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Tongyu Tang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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11
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Chen H, Fu X, Wu X, Zhao J, Qiu F, Wang Z, Wang Z, Chen X, Xie D, Huang J, Fan J, Yang X, Song Y, Li J, He D, Xiao G, Lu A, Liang C. Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis. Bone Res 2024; 12:31. [PMID: 38782893 PMCID: PMC11116389 DOI: 10.1038/s41413-024-00336-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/18/2024] [Accepted: 04/07/2024] [Indexed: 05/25/2024] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.
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Affiliation(s)
- Hongzhen Chen
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
| | - Xuekun Fu
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Xiaohao Wu
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Division of Immunology and Rheumatology, Stanford University, Stanford, CA, 94305, USA
- VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA
| | - Junyi Zhao
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
| | - Fang Qiu
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Zhenghong Wang
- Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhuqian Wang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Xinxin Chen
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
| | - Duoli Xie
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Jie Huang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Junyu Fan
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu Yang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Yi Song
- Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Jie Li
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Dongyi He
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guozhi Xiao
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
| | - Aiping Lu
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, 510006, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| | - Chao Liang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055, China.
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China.
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.
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12
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Turizo-Smith AD, Córdoba-Hernandez S, Mejía-Guarnizo LV, Monroy-Camacho PS, Rodríguez-García JA. Inflammation and cancer: friend or foe? Front Pharmacol 2024; 15:1385479. [PMID: 38799159 PMCID: PMC11117078 DOI: 10.3389/fphar.2024.1385479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.
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Affiliation(s)
- Andrés David Turizo-Smith
- Doctorado en Oncología, Departamento de Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
- Semillero de Investigación en Cannabis y Derivados (SICAD), Universidad Nacional de Colombia, Bogotá, Colombia
| | - Samantha Córdoba-Hernandez
- Semillero de Investigación en Cannabis y Derivados (SICAD), Universidad Nacional de Colombia, Bogotá, Colombia
| | - Lidy Vannessa Mejía-Guarnizo
- Facultad de Ciencias, Maestría en Ciencias, Microbiología, Universidad Nacional de Colombia, Bogotá, Colombia
- Grupo de investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá, Colombia
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13
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Yang Y, Jin C, Yeo A, Jin B. Multiple Factors Determine the Oncolytic or Carcinogenic Effects of TLRs Activation in Cancer. J Immunol Res 2024; 2024:1-28. [DOI: 10.1155/2024/1111551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Toll-like receptors (TLRs) belong to a germline-encoded protein family. These are pattern recognition receptors. They sense pathogen-associated molecular patterns (PAMPs). When this occurs, activation of the NF-ĸB pathway follows. This triggers the innate immune response of the host. The consequent inflammatory cytokine response usually contributes to the elimination of the pathogen. Activation of TLRs also induces an adaptive immune response by a cross-prime mechanism. This mechanism is employed in cancer immunotherapy. Using TLR ligands as adjuvants induces upregulation of costimulatory signals which in turn activates a cytotoxic leukocyte response against cancer cells. However, TLRs are also overexpressed in human cancer cells resulting in increased cell proliferation, migration, invasion, and angiogenesis. An intracellular adaptor, myeloid differentiation factor 88 (MyD88) probably mediates this process. MyD88 is intimately involved with all TLRs except TLR3. One consequence of the interaction between a TLR and MyD88 is activation of NF-ĸB. In this context of a variety of proinflammtory cytokines being produced, chronic inflammation may result. Inflammation is an important protective mechanism. However, chronic inflammation is also involved in carcinogenesis. Activation of NF-ĸB inhibits apoptosis and under certain circumstances, tumor cell survival. In this review, the potential therapeutic value of TLRs in immunotherapy and its role in oncogenesis are explored. The emerging use of artificial intelligence is mentioned.
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Affiliation(s)
- Yingxiang Yang
- Department of Hepato-Pancreato-Biliary Surgery, The Sixth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Chengyue Jin
- Beijing Arion Cancer Center, Beijing 100070, China
| | | | - Bo Jin
- Senior Department of Gastroenterology, The First Medical Center of PLA General Hospital, Beijing 100853, China
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14
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Zhang J, Chen C, Yan W, Fu Y. New sights of immunometabolism and agent progress in colitis associated colorectal cancer. Front Pharmacol 2024; 14:1303913. [PMID: 38273841 PMCID: PMC10808433 DOI: 10.3389/fphar.2023.1303913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.
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Affiliation(s)
- Jingyue Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoyue Chen
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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15
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Li C, Lu G, Jiang Y, Su H, Li C. A Novel Etanercept-loaded Nano-emulsion for Targeted Treatment of Inflammatory Arthritis via Draining Lymph Node. Curr Drug Deliv 2024; 21:1106-1113. [PMID: 37565561 DOI: 10.2174/1567201821666230810115230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/23/2023] [Accepted: 05/16/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production. AIM The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG2000 and Ca(OH)2. METHODS A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG2000 and Ca(OH)2 were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model. RESULTS Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN. CONCLUSION NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.
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Affiliation(s)
- Chenglong Li
- Department of Pharmacy, Deyang People's Hospital, Deyang 618000, China
| | - Guanting Lu
- Laboratory of Translational Medicine Research, Department of Pathology, Deyang People's Hospital, Deyang 618000, China
- Key Laboratory of Tumor Molecular Research of Deyang, Deyang People's Hospital, Deyang 618000, China
| | - Yue Jiang
- Department of Pharmacy, Deyang People's Hospital, Deyang 618000, China
| | - Huaiyu Su
- Department of Pharmacy, Deyang People's Hospital, Deyang 618000, China
| | - Chen Li
- Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, Chengdu 610000, China
- School of Medicine, University of Electronic Science and Technology, Chengdu 610000, China
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16
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Siegmund D, Zaitseva O, Wajant H. Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling. Front Cell Dev Biol 2023; 11:1267837. [PMID: 38020877 PMCID: PMC10657838 DOI: 10.3389/fcell.2023.1267837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Tumor necrosis factor (TNF) receptor 1 (TNFR1), TNFR2 and fibroblast growth factor-inducible 14 (Fn14) belong to the TNF receptor superfamily (TNFRSF). From a structural point of view, TNFR1 is a prototypic death domain (DD)-containing receptor. In contrast to other prominent death receptors, such as CD95/Fas and the two TRAIL death receptors DR4 and DR5, however, liganded TNFR1 does not instruct the formation of a plasma membrane-associated death inducing signaling complex converting procaspase-8 into highly active mature heterotetrameric caspase-8 molecules. Instead, liganded TNFR1 recruits the DD-containing cytoplasmic signaling proteins TRADD and RIPK1 and empowers these proteins to trigger cell death signaling by cytosolic complexes after their release from the TNFR1 signaling complex. The activity and quality (apoptosis versus necroptosis) of TNF-induced cell death signaling is controlled by caspase-8, the caspase-8 regulatory FLIP proteins, TRAF2, RIPK1 and the RIPK1-ubiquitinating E3 ligases cIAP1 and cIAP2. TNFR2 and Fn14 efficiently recruit TRAF2 along with the TRAF2 binding partners cIAP1 and cIAP2 and can thereby limit the availability of these molecules for other TRAF2/cIAP1/2-utilizing proteins including TNFR1. Accordingly, at the cellular level engagement of TNFR2 or Fn14 inhibits TNFR1-induced RIPK1-mediated effects reaching from activation of the classical NFκB pathway to induction of apoptosis and necroptosis. In this review, we summarize the effects of TNFR2- and Fn14-mediated depletion of TRAF2 and the cIAP1/2 on TNFR1 signaling at the molecular level and discuss the consequences this has in vivo.
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Affiliation(s)
| | | | - Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
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17
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Shimomura K, Hattori N, Iida N, Muranaka Y, Sato K, Shiraishi Y, Arai Y, Hama N, Shibata T, Narushima D, Kato M, Takamaru H, Okamoto K, Takeda H. Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development. Nat Commun 2023; 14:6514. [PMID: 37845228 PMCID: PMC10579371 DOI: 10.1038/s41467-023-42228-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/29/2023] [Indexed: 10/18/2023] Open
Abstract
Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.
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Affiliation(s)
- Kana Shimomura
- The Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Naoko Hattori
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Naoko Iida
- Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Yukari Muranaka
- The Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kotomi Sato
- The Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuichi Shiraishi
- Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasuhito Arai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Natsuko Hama
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Daichi Narushima
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
| | - Mamoru Kato
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Koji Okamoto
- Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan
| | - Haruna Takeda
- The Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan.
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18
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Zhao X, Stein KR, Chen V, Griffin ME, Lairson LL, Hang HC. Chemoproteomics reveals microbiota-derived aromatic monoamine agonists for GPRC5A. Nat Chem Biol 2023; 19:1205-1214. [PMID: 37248411 DOI: 10.1038/s41589-023-01328-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/06/2023] [Indexed: 05/31/2023]
Abstract
The microbiota generates diverse metabolites to modulate host physiology and disease, but their protein targets and mechanisms of action have not been fully elucidated. To address this challenge, we explored microbiota-derived indole metabolites and developed photoaffinity chemical reporters for proteomic studies. We identified many potential indole metabolite-interacting proteins, including metabolic enzymes, transporters, immune sensors and G protein-coupled receptors. Notably, we discovered that aromatic monoamines can bind the orphan receptor GPRC5A and stimulate β-arrestin recruitment. Metabolomic and functional profiling also revealed specific amino acid decarboxylase-expressing microbiota species that produce aromatic monoamine agonists for GPRC5A-β-arrestin recruitment. Our analysis of synthetic aromatic monoamine derivatives identified 7-fluorotryptamine as a more potent agonist of GPRC5A. These results highlight the utility of chemoproteomics to identify microbiota metabolite-interacting proteins and the development of small-molecule agonists for orphan receptors.
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Affiliation(s)
- Xiaohui Zhao
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA
| | - Kathryn R Stein
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA
| | - Victor Chen
- Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York City, NY, USA
| | - Matthew E Griffin
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA
| | - Luke L Lairson
- Department of Chemistry, Scripps Research, La Jolla, CA, USA
| | - Howard C Hang
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA.
- Department of Chemistry, Scripps Research, La Jolla, CA, USA.
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Ma C, Zhang Z, Li T, Tao Y, Zhu G, Xu L, Ju Y, Huang X, Zhai J, Wang X. Colonic expression of glutathione S-transferase alpha 4 and 4-hydroxynonenal adducts is correlated with the pathology of murine colitis-associated cancer. Heliyon 2023; 9:e19815. [PMID: 37810110 PMCID: PMC10559223 DOI: 10.1016/j.heliyon.2023.e19815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/30/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione S-transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC.
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Affiliation(s)
- Chunhua Ma
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Zhanhu Zhang
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Tianqi Li
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Yumei Tao
- Department of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Guoxiang Zhu
- Department of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Lili Xu
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Yuanyuan Ju
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Xu Huang
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
| | - Jinyun Zhai
- Department of Medical Experimental Technology, Nantong University Xinglin College, Nantong, China
| | - Xingmin Wang
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, China
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20
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Petsakou A, Liu Y, Liu Y, Comjean A, Hu Y, Perrimon N. Epithelial Ca 2+ waves triggered by enteric neurons heal the gut. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.14.553227. [PMID: 37645990 PMCID: PMC10461974 DOI: 10.1101/2023.08.14.553227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer. We used the Drosophila midgut to investigate this question and discovered that during regeneration a subpopulation of cholinergic enteric neurons triggers Ca2+ currents among enterocytes to promote return of the epithelium to homeostasis. Specifically, we found that down-regulation of the cholinergic enzyme Acetylcholinesterase in the epithelium enables acetylcholine from defined enteric neurons, referred as ARCENs, to activate nicotinic receptors in enterocytes found near ARCEN-innervations. This activation triggers high Ca2+ influx that spreads in the epithelium through Inx2/Inx7 gap junctions promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki activation and increase of inflammatory cytokines together with hyperplasia, reminiscent of inflammatory bowel diseases. Altogether, we found that during gut regeneration the conserved cholinergic pathway facilitates epithelial Ca2+ waves that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration which advance the current understanding of how a tissue returns to its homeostatic state after injury and could ultimately help existing therapeutics.
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Affiliation(s)
| | - Yifang Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Ying Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Aram Comjean
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Yanhui Hu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Norbert Perrimon
- Department of Genetics, Harvard Medical School, Boston, USA
- Howard Hughes Medical Institute, Boston, USA
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21
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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Lee M, Kim YS, Lim S, Shin SH, Kim I, Kim J, Choi M, Kim JH, Koh SJ, Park JW, Shin HW. Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development. Nat Commun 2023; 14:2363. [PMID: 37185280 PMCID: PMC10130090 DOI: 10.1038/s41467-023-38080-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.
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Affiliation(s)
- Mingyu Lee
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, USA
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yi-Sook Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Suha Lim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Hyun Shin
- Hanmi Research Center, Hanmi Pharmaceutical Co. Ltd., 550 Dongtangiheung-ro, Hwaseong-si, 18469, Gyeonggi-do, South Korea
| | - Iljin Kim
- Department of Pharmacology, Inha University College of Medicine, Incheon, South Korea
| | - Jiyoung Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Min Choi
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Seong-Joon Koh
- Liver Research Institute and Seoul National University College of Medicine, Seoul, South Korea
| | - Jong-Wan Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyun-Woo Shin
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
- Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea.
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, South Korea.
- Sensory Organ Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
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23
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Wei W, Wang J, Huang P, Gou S, Yu D, Zong L. Tumor necrosis factor-α induces proliferation and reduces apoptosis of colorectal cancer cells through STAT3 activation. Immunogenetics 2023; 75:161-169. [PMID: 36933092 DOI: 10.1007/s00251-023-01302-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 02/14/2023] [Indexed: 03/19/2023]
Abstract
Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory factor that plays an important role in establishing a complicated connection between inflammation and cancer. TNF-α promotes tumor proliferation, migration, invasion, and angiogenesis according to numerous studies. Studies have shown the significant role of STAT3, a downstream transcription factor of another important inflammatory cytokine, IL-6 in the development and progression of different tumors especially colorectal cancer. In the present study, we investigated whether TNF-α has a role in proliferation and apoptosis of colorectal cancer cells through STAT3 activation. HCT116 cell line as human colorectal cancer cells was used in this study. Major assays were MTT assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, and ELISA. Results showed that TNF-α significantly increased the phosphorylation of STAT3 and expression of all the STAT3 target genes related to cell proliferation, survival, and metastasis compared with control. Moreover, our data showed that the STAT3 phosphorylation and expression of its target genes significantly were reduced in the presence of TNF-α + STA-21 compared with TNF-α-treated group demonstrating that the increase in genes expression partially was due to the TNF-α-induced STAT3 activation. On the other hand, STAT3 phosphorylation and mRNA levels of its target genes were partially decreased in the presence of TNF-α + IL-6R supporting the indirect pathway of STAT3 activation by TNF-α through inducing IL-6 production in cancer cells. Given the growing evidence for STAT3 as a key mediator of inflammation-induced colon cancer, our findings support further investigation of STAT3 inhibitors as potential cancer therapies.
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Affiliation(s)
- Wei Wei
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Juanhong Wang
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Pu Huang
- Department of Pathology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi, 710021, People's Republic of China
| | - Siqi Gou
- Department of Pathology, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Daihua Yu
- Department of Critical Care Medicine, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China
| | - Lei Zong
- Department of Critical Care Medicine, Xi'an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, 710018, People's Republic of China.
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Zhang M, Li X, Zhang Q, Yang J, Liu G. Roles of macrophages on ulcerative colitis and colitis-associated colorectal cancer. Front Immunol 2023; 14:1103617. [PMID: 37006260 PMCID: PMC10062481 DOI: 10.3389/fimmu.2023.1103617] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Colitis-associated colorectal cancer is the most serious complication of ulcerative colitis. Long-term chronic inflammation increases the incidence of CAC in UC patients. Compared with sporadic colorectal cancer, CAC means multiple lesions, worse pathological type and worse prognosis. Macrophage is a kind of innate immune cell, which play an important role both in inflammatory response and tumor immunity. Macrophages are polarized into two phenotypes under different conditions: M1 and M2. In UC, enhanced macrophage infiltration produces a large number of inflammatory cytokines, which promote tumorigenesis of UC. M1 polarization has an anti-tumor effect after CAC formation, whereas M2 polarization promotes tumor growth. M2 polarization plays a tumor-promoting role. Some drugs have been shown to that prevent and treat CAC effectively by targeting macrophages.
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25
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Kaya MM, Kaya İ, Nazıroğlu M. Transient receptor potential channel stimulation induced oxidative stress and apoptosis in the colon of mice with colitis-associated colon cancer: modulator role of Sambucus ebulus L. Mol Biol Rep 2023; 50:2207-2220. [PMID: 36565417 DOI: 10.1007/s11033-022-08200-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 12/12/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Increased Ca2+ entry causes an increase in tumor cell proliferation, apoptosis, cytosolic reactive free oxygen species (cyROS), and mitochondrial ROS (miROS) in tumor cells. The cyROS and miROS stimulate the cation channels, including the TRPA1, TRPM2, and TRPV1. Sambucus ebulus L (SEB) (Dwarf Elder) induced both antioxidant and anticancer effects in the human hepatocarcinoma and human colon carcinoma cancer cell lines. We investigated the etiology of colorectal cancer and the impact of three channels, as well as the protective effects of SEB on apoptosis, cyROS, and miROS in the colon of mice with colitis-associated colon cancer (AOM/DSS). METHODS A total 28 mice were equally divided into four groups as control, SEB (100 mg/kg/day for 14 days), AOM/DSS, and SEB + AOM/DSS. Azoxymethane/dextran sulfate sodium-induced colon cancer associated with colitis was induced in the AOM/DSS groups within 10 weeks. At the end of the experiments, the colon samples were removed from the mice. RESULTS The protein bands of caspase - 3, TRPA1, TRPM2, and TRPV1 were increased by the treatments of AOM/DSS. The levels of apoptosis, cyROS, cleaved caspase - 3, and cleaved caspase - 9, as well as the depolarization of the mitochondrial membrane, all increased in the AOM/DSS group. Although they were reduced in the SEB and AOM/DSS + SEB groups by the treatments of SEB, TRPA1 (AP18), TRPM2 (ACA), and TRPV1 (capsazepine) antagonists, the apoptotic and oxidant values were further elevated in the AOM/DSS group by the treatments of TRPA1 (cinnamaldehyde), TRPM2 (H2O2), and TRPV1 (capsaicin) agonists. CONCLUSION The activations of TRPA1, TRPM2, and TRPV1 channels induced the increase of apoptotic and oxidant actions in the colon cancer cells, although their inhibition via SEB treatment decreased the actions. Hence, TRPA1, TRPM2, and TRPV1 activations could be used as effective agents in the treatment of colon tumors.
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Affiliation(s)
- Müge Mavioğlu Kaya
- Department of Molecular Biology and Genetics, Faculty of Science, Kafkas University, 36100, Kars, Turkey
| | - İnan Kaya
- Department of Biology, Faculty of Science, Kafkas University, 36100, Kars, Turkey
| | - Mustafa Nazıroğlu
- Neuroscience Research Center, Suleyman Demirel University, 32260, Isparta, Turkey. .,BSN Health, Analysis and Innovation Ltd, Türkiye, 32260, Isparta, Turkey. .,Department of Biophysics Faculty of Medicine, Suleyman Demirel University, 32260, Isparta, Türkiye.
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26
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Bai X, Wei H, Liu W, Coker OO, Gou H, Liu C, Zhao L, Li C, Zhou Y, Wang G, Kang W, Ng EKW, Yu J. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut 2022; 71:2439-2450. [PMID: 35387878 PMCID: PMC9664112 DOI: 10.1136/gutjnl-2021-325021] [Citation(s) in RCA: 143] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 03/10/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites. DESIGN Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice. RESULTS Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal‑regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium. CONCLUSION The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.
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Affiliation(s)
- Xiaowu Bai
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China,Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Hong Wei
- Department of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Weixin Liu
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Olabisi Oluwabukola Coker
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Hongyan Gou
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Changan Liu
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Liuyang Zhao
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Chuangen Li
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Yunfei Zhou
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Guoping Wang
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Enders Kwok-wai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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Huang Z, Gong L, Jin Y, Stanton C, Ross RP, Zhao J, Yang B, Chen W. Different Effects of Different Lactobacillus acidophilus Strains on DSS-Induced Colitis. Int J Mol Sci 2022; 23:ijms232314841. [PMID: 36499169 PMCID: PMC9738729 DOI: 10.3390/ijms232314841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a worldwide chronic intestinal inflammatory immune-related disease. In this study, mice with dextran sulfate sodium (DSS)-induced colitis were used to evaluate the effect of Lactobacillus acidophilus on colitis. The results revealed that L. acidophilus CCFM137 and FAHWH11L56 show potential for relieving colitis symptoms, while L. acidophilus FGSYC48L79 did not show a protective effect. Moreover, L. acidophilus NCFM and FAHWH11L56 showed similar effects on various indicators of DSS-induced colitis, increasing the IL-10 and IL-17 in the colon, and modifying the CCL2/CCR2 axis and CCL3/CCR1 axis. For L. acidophilus CCFM137, its effects on colitis were different from the above two strains. Moreover, L. acidophilus FGSYC48L79 had negative effects on colitis by increasing the abundance of harmful bacteria in the gut microbiota and may promote the signaling of chemokines and their receptors. This may be related to its special genome compared to the other strains.
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Affiliation(s)
- Zheng Huang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Lei Gong
- Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi 214122, China
- Correspondence: (L.G.); (B.Y.); Tel.: +86-510-8591-2155 (B.Y.)
| | - Yan Jin
- Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi 214122, China
| | - Catherine Stanton
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- APC Microbiome Ireland, University College Cork, T12 K8AF Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Fermoy, P61 C996 Co. Cork, Ireland
| | - Reynolds Paul Ross
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- APC Microbiome Ireland, University College Cork, T12 K8AF Cork, Ireland
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Bo Yang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- Correspondence: (L.G.); (B.Y.); Tel.: +86-510-8591-2155 (B.Y.)
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
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Han YK, Xu YC, Luo Z, Zhao T, Zheng H, Tan XY. Fish Meal Replacement by Mixed Plant Protein in the Diets for Juvenile Yellow Catfish Pelteobagrus fulvidraco: Effects on Growth Performance and Health Status. AQUACULTURE NUTRITION 2022; 2022:2677885. [PMID: 36860441 PMCID: PMC9973144 DOI: 10.1155/2022/2677885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/19/2022] [Accepted: 10/31/2022] [Indexed: 06/18/2023]
Abstract
Increasing dietary replacement levels of fish meal by alternative plant proteins are of value for aquaculture. Here, a 10-week feeding experiment was undertaken to explore the effects of fish meal replacement by mixed plant protein (at a 2 : 3 ratio of cottonseed meal to rapeseed meal) on growth performance, oxidative and inflammatory responses, and mTOR pathway of yellow catfish Pelteobagrus fulvidraco. Yellow catfish (2.38 ± 0.1 g, mean ± SEM) were randomly divided into 15 indoors fiberglass tanks, 30 fish each tank, and fed five isonitrogenous (44% crude protein) and isolipidic (9% crude fat) diets with fish meal replaced by mixed plant protein at 0% (the control), 10% (RM10), 20% (RM20), 30% (RM30), and 40% (RM40), respectively. Among five groups, fish fed the control, and RM10 diets tended to have higher growth performance, higher protein content, and lower lipid content in livers. Dietary mixed plant protein substitute increased hepatic free gossypol content and damaged liver histology and reduced the serum total essential amino acids, total nonessential amino acids, and total amino acid contents. Yellow catfish fed the control, and RM10 diets tended to have higher antioxidant capacity. Dietary mixed plant protein replacement tended to promote proinflammatory responses and inhibited mTOR pathway. Based on the second regression analysis of SGR against mixed plant protein substitutes, the optimal replacement level of fish meal by mixed plant protein was 8.7%.
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Affiliation(s)
- Ya-Kang Han
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
| | - Yi-Chuang Xu
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhi Luo
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
| | - Tao Zhao
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
| | - Hua Zheng
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiao-Ying Tan
- Laboratory of Nutrition and Feed Formulation for Aquatic Economic Animals, Huazhong Agricultural University, Wuhan 430070, China
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29
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Zhang H, Cui Z, Pan T, Hu H, He R, Yi M, Sun W, Gao R, Wang H, Ma X, Peng Q, Feng X, Liang S, Du Y, Wang C. RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1796-1805. [PMID: 36130827 PMCID: PMC9553791 DOI: 10.4049/jimmunol.2200229] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/08/2022] [Indexed: 01/04/2023]
Abstract
The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer.
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Affiliation(s)
- Huazhi Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Cui
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Pan
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Huijun Hu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ruirui He
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Ming Yi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Wanwei Sun
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ru Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Heping Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojian Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Qianwen Peng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiong Feng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | | | - Yanyun Du
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
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Vitali L, Merlini A, Galvagno F, Proment A, Sangiolo D. Biological and Exploitable Crossroads for the Immune Response in Cancer and COVID-19. Biomedicines 2022; 10:2628. [PMID: 36289890 PMCID: PMC9599827 DOI: 10.3390/biomedicines10102628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/05/2022] [Accepted: 10/14/2022] [Indexed: 12/15/2022] Open
Abstract
The outbreak of novel coronavirus disease 2019 (COVID-19) has exacted a disproportionate toll on cancer patients. The effects of anticancer treatments and cancer patients' characteristics shared significant responsibilities for this dismal outcome; however, the underlying immunopathological mechanisms are far from being completely understood. Indeed, despite their different etiologies, SARS-CoV-2 infection and cancer unexpectedly share relevant immunobiological connections. In the pathogenesis and natural history of both conditions, there emerges the centrality of the immune response, orchestrating the timed appearance, functional and dysfunctional roles of multiple effectors in acute and chronic phases. A significant number (more than 600) of observational and interventional studies have explored the interconnections between COVID-19 and cancer, focusing on aspects as diverse as psychological implications and prognostic factors, with more than 4000 manuscripts published so far. In this review, we reported and discussed the dynamic behavior of the main cytokines and immune system signaling pathways involved in acute vs. early, and chronic vs. advanced stages of SARS-CoV-2 infection and cancer. We highlighted the biological similarities and active connections within these dynamic disease scenarios, exploring and speculating on possible therapeutic crossroads from one setting to the other.
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Affiliation(s)
- Letizia Vitali
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Alessandra Merlini
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Federica Galvagno
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Alessia Proment
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Dario Sangiolo
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
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31
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Chen XQ, Mao JY, Wang CS, Li WB, Han TT, Lv K, Li JN. CYP24A1 Involvement in Inflammatory Factor Regulation Occurs via the Wnt Signaling Pathway. Curr Med Sci 2022; 42:1022-1032. [PMID: 36255661 DOI: 10.1007/s11596-022-2564-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 12/10/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE While the upregulation of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene expression has been reported in colon cancer, its role in tumorigenesis remains largely unknown. In this study, we aimed to investigate the involvement of CYP24A1 in Wnt pathway regulation via the nuclear factor kappa B (NF-κB) pathway. METHODS The human colon cancer cell lines HCT-116 and Caco-2 were subjected to stimulation with interleukin-6 (IL-6) as well as tumor necrosis factor alpha (TNF-α), with subsequent treatment using the NF-κB pathway-specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). Furthermore, CYP24A1 expression was subjected to knockdown via the use of small interfering RNA (siRNA). Subsequently, NF-κB pathway activation was determined by an electrophoretic mobility shift assay, and the transcriptional activity of β-catenin was determined by a dual-luciferase reporter assay. A mouse ulcerative colitis (UC)-associated carcinogenesis model was established, wherein TNF-α and the NF-κB pathway were blocked by anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides, respectively. Then the tumor size and protein level of CYP24A1 were determined. RESULTS IL-6 and TNF-α upregulated CYP24A1 expression and activated the NF-κB pathway in colon cancer cells. PDTC significantly inhibited this increase in CYP24A1 expression. Additionally, knockdown of CYP24A1 expression by siRNA could partially antagonize Wnt pathway activation. Upregulated CYP24A1 expression was observed in the colonic epithelial cells of UC-associated carcinoma mouse models. Anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides decreased the tumor size and suppressed CYP24A1 expression. CONCLUSION Taken together, this study suggests that inflammatory factors may increase CYP24A1 expression via NF-κB pathway activation, which in turn stimulates Wnt signaling.
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Affiliation(s)
- Xue-Qi Chen
- Department of Medical Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100730, China
| | - Jia-Yu Mao
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100730, China
| | - Chun-Saier Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Wen-Bin Li
- Department of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatrics Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Tao-Tao Han
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science; Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Ke Lv
- Department of Medical Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Jing-Nan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science; Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Science, Beijing, 100730, China.
- Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Science, Beijing, 100730, China.
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Evaluation of Tumor Necrosis Factor-Alpha Gene (−308 G/A, −238 G/A and −857 C/T) Polymorphisms and the Risk of Gastric Cancer in Eastern Indian Population. GASTROENTEROLOGY INSIGHTS 2022. [DOI: 10.3390/gastroent13040034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Introduction: Gastric cancer (GC) is one of the leading causes of cancer-related decimations worldwide. The gastric infection at both the stomach and duodenum with Helicobacter pylori causes inflammation by the tumor necrosis factor-alpha (TNF-α). The aim of the study was to associate and evaluate the three TNF-α gene polymorphisms at positions −308 G/A, −238 G/A, and −857 C/T with the risk of GC. Methods: A total of 156 individuals (consecutively diagnosed 95 GC patients and 61 controls) above the age of 18 years were enrolled in the study. Healthy individuals with normal upper gastrointestinal endoscopy (UGIE) irrespective of their family history of GC or peptic ulcer were included as controls. The cited three TNF-α gene polymorphisms were evaluated using polymerase chain reaction-restriction fragment length polymorphism (RFLP). Results: There was no significant difference in the distribution of gene polymorphisms as genetic factors, TNF-α−308 GA/AA (22.1% vs. 14.8%, p = 0.2), TNF-α−238 GA/AA (21% vs. 19.6%, p = 0.8), and TNF-α−857 CT/TT (8.4% vs. 11.5%, p = 0.5), between GC cases and healthy controls. A subgroup analysis of H. pylori-positive patients showed that there was no significant difference in the distribution of GA/AA polymorphisms in TNF-α−308 (15(45.5%) vs. 3(23%); p = 0.17) and −238 (12(36.3%) vs. 2(15.4%); p = 0.17), and the distribution of TT/CT −857 CT/TT (13(39.4%) vs. 2(15.4%); p = 0.13), among the GC cases and controls. Conclusion: The statistical comparisons of GA/AA vs. GG genotypes at −308 (with OR = 1.6, 95% CI: 0.6–3.8), −238 (OR = 1.09, 95% CI: 0.4–2.4) and TT/CT vs. CC genotypes at −857 (OR = 0.7, 95% CI: 0.2–2.1) did not suggest any association of TNF-α with GC in the population herein. Hence, the TNF-α (−308 G/A, −238 G/A and −857 C/T) may not be the associating factor for GC incidence determined by the PCR–RFLP method.
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Essential Roles of Peroxiredoxin IV in Inflammation and Cancer. Molecules 2022; 27:molecules27196513. [PMID: 36235049 PMCID: PMC9573489 DOI: 10.3390/molecules27196513] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/21/2022] [Accepted: 09/29/2022] [Indexed: 11/22/2022] Open
Abstract
Peroxiredoxin IV (Prx4) is a 2-Cysteine peroxidase with ubiquitous expression in human tissues. Prx4 scavenges hydrogen peroxide and participates in oxidative protein folding in the endoplasmic reticulum. In addition, Prx4 is secreted outside the cell. Prx4 is upregulated in several cancers and is a potential therapeutic target. We have summarized historical and recent advances in the structure, function and biological roles of Prx4, focusing on inflammatory diseases and cancer. Oxidative stress is known to activate pro-inflammatory pathways. Chronic inflammation is a risk factor for cancer development. Hence, redox enzymes such as Prx4 are important players in the crosstalk between inflammation and cancer. Understanding molecular mechanisms of regulation of Prx4 expression and associated signaling pathways in normal physiological and disease conditions should reveal new therapeutic strategies. Thus, although Prx4 is a promising therapeutic target for inflammatory diseases and cancer, further research needs to be conducted to bridge the gap to clinical application.
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Liu Y, Tang Q, Feng J, Liu J, Tang C, Yan M, Zhou S, Liu L, Zhou J, Zhang J. Effects of molecular weight on intestinal anti-inflammatory activities of β-D-glucan from Ganoderma lucidum. Front Nutr 2022; 9:1028727. [PMID: 36245525 PMCID: PMC9557179 DOI: 10.3389/fnut.2022.1028727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
To investigate the influence of molecular weight (Mw) on the anti-inflammatory activity of β-D-glucan from Ganoderma lucidum, ultrasonic irradiation was applied to treat the β-D-glucan (GLP, 2.42 × 106 g/mol) solution to obtain two degraded fractions with molecular weight of 6.53 × 105 g/mol (GLPC) and 3.49 × 104 g/mol (GLPN). Structural analysis proved that the degraded fractions possessed similar repeated units with the original β-D-glucan. The in vitro anti-inflammatory activity studies showed that all fractions could significantly inhibit LPS-induced expression of cytokines including TNF-α, IL-8, MIF and MCP-1 in Caco-2 cells at certain concentrations. Moreover, GLPC and GLPN exhibited better anti-inflammatory activity than GLPC. The intestinal anti-inflammatory activity evaluated by dextran sulfate sodium (DSS)—induced colitis mice model showed that intragastric administration of GLPN (lower Mw fraction) could significantly recover inflamed tissues of mice. Compared with GLP and GLPC, GLPN exhibited stronger ability to inhibit the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). The results revealed that Mw of β-D-glucan influenced its anti-inflammatory activity and decreasing of Mw would improve the activity, which provided evidence for the potential use of β-D-glucan from G. lucidum as anti-colitis ingredients.
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Affiliation(s)
- Yanfang Liu
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Qingjiu Tang
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Jie Feng
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Jing Liu
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Chuanhong Tang
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Mengqiu Yan
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Shuai Zhou
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Liping Liu
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
| | - Jing Zhou
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
- Shanghai Baixin Bio-Tech Co., Ltd., Shanghai, China
| | - Jingsong Zhang
- Institute of Edible Fungi, Shanghai Academy of Agricultural Sciences, Ministry of Agriculture, Shanghai, China
- Key Laboratory of Edible Fungi Resources and Utilization (South), Ministry of Agriculture, Shanghai, China
- National Engineering Research Center of Edible Fungi, Shanghai, China
- *Correspondence: Jingsong Zhang
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Ghilas S, O’Keefe R, Mielke LA, Raghu D, Buchert M, Ernst M. Crosstalk between epithelium, myeloid and innate lymphoid cells during gut homeostasis and disease. Front Immunol 2022; 13:944982. [PMID: 36189323 PMCID: PMC9524271 DOI: 10.3389/fimmu.2022.944982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/29/2022] [Indexed: 12/05/2022] Open
Abstract
The gut epithelium not only provides a physical barrier to separate a noxious outside from a sterile inside but also allows for highly regulated interactions between bacteria and their products, and components of the immune system. Homeostatic maintenance of an intact epithelial barrier is paramount to health, requiring an intricately regulated and highly adaptive response of various cells of the immune system. Prolonged homeostatic imbalance can result in chronic inflammation, tumorigenesis and inefficient antitumor immune control. Here we provide an update on the role of innate lymphoid cells, macrophages and dendritic cells, which collectively play a critical role in epithelial barrier maintenance and provide an important linkage between the classical innate and adaptive arm of the immune system. These interactions modify the capacity of the gut epithelium to undergo continuous renewal, safeguard against tumor formation and provide feedback to the gut microbiome, which acts as a seminal contributor to cellular homeostasis of the gut.
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Affiliation(s)
- Sonia Ghilas
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Ryan O’Keefe
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Lisa Anna Mielke
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Dinesh Raghu
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Michael Buchert
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
| | - Matthias Ernst
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
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36
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Pu W, Su Z, Wazir J, Zhao C, Wei L, Wang R, Chen Q, Zheng S, Zhang S, Wang H. Protective effect of α7 nicotinic acetylcholine receptor activation on experimental colitis and its mechanism. Mol Med 2022; 28:104. [PMID: 36058917 PMCID: PMC9441089 DOI: 10.1186/s10020-022-00532-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) is a common chronic remitting disease with no satisfactory treatment. The aim of this study was to investigate the protective effect of α7 nicotinic acetylcholine receptor (α7nAChR), and to determine the underlying mechanism of its activity. Methods The expression and distribution of α7nAChR in the intestinal tissue of patients with ulcerative colitis and Crohn’s disease were analyzed. The effects of vagal excitation on murine experimental colitis were investigated. The colitis model was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). The therapeutic group received treatment with the α7nAChR agonist PNU-282987 by intraperitoneal injection. Results Our results showed that there was significantly increased expression of α7nAChR in colitis and Crohn’s disease intestinal tissue, and its expression was mainly located in macrophages and neutrophils, which were extensively infiltrated in the disease status. Treatment with an α7nAChR agonist potently ameliorated the DSS-induced illness state, including weight loss, stool consistency, bleeding, colon shortening, and colon histological injury. α7nAChR agonist exerted anti-inflammatory effects in DSS colitis mice by suppressing the secretion of multiple types of proinflammatory factors, such as IL6, TNFα, and IL1β, and it also inhibited the colonic infiltration of inflammatory cells by blocking the DSS-induced overactivation of the NF-κB and MAPK signaling pathways. Mechanistically, activation of α7nAChR decreased the number of infiltrated M1 macrophages in the colitis intestine and inhibited the phagocytosis ability of macrophages, which were activated in response to LPS stimulation. Conclusion Thus, an α7nAChR agonist ameliorated colonic pathology and inflammation in DSS-induced colitis mice by blocking the activation of inflammatory M1 macrophages.
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Affiliation(s)
- Wenyuan Pu
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Zhenzi Su
- The Affiliated Suqian Hospital of Xuzhou Medical University and Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, 223800, China
| | - Junaid Wazir
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Chen Zhao
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Lulu Wei
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Ranran Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Qiyi Chen
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University, Shanghai, 200072, China
| | - Saifang Zheng
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China
| | - Shaoyi Zhang
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
| | - Hongwei Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
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Lee HM, Lee HJ, Chang JE. Inflammatory Cytokine: An Attractive Target for Cancer Treatment. Biomedicines 2022; 10:biomedicines10092116. [PMID: 36140220 PMCID: PMC9495935 DOI: 10.3390/biomedicines10092116] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/28/2022] Open
Abstract
The relationship between inflammation and cancer has attracted attention for a long time. The inflammatory tumor microenvironment consists of inflammatory cells, chemokines, cytokines, and signaling pathways. Among them, inflammatory cytokines play an especially pivotal role in cancer development, prognosis, and treatment. Interleukins, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interferons, and vascular endothelial growth factor (VEGF) are the representative inflammatory cytokines in various cancers, which may promote or inhibit cancer progression. The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival. In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines. The related cytokines and their effects on each cancer’s development and prognosis were summarized. In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment.
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38
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Goodla L, Xue X. The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis. Cells 2022; 11:2313. [PMID: 35954156 PMCID: PMC9367504 DOI: 10.3390/cells11152313] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal veins receiving blood from the digestive tract. Understanding the cellular and molecular mechanisms of hepatic metastases is of dire need for the development of potent targeted therapeutics. Immuno-signaling molecules including cytokines and chemokines play a pivotal role in hepatic metastases from CRC. This brief review discusses the involvement of three representative cytokines (TNF-α, IL-6 and IL-1β), a lipid molecule PGE2 and two chemokines (CXCL1 and CXCL2) in the process of CRC liver metastases.
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Affiliation(s)
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;
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Kim HY, Seo JE, Lee H, Bae CH, Ha KT, Kim S. Rumex japonicus Houtt. Extract Suppresses Colitis-Associated Colorectal Cancer by Regulating Inflammation and Tight-Junction Integrity in Mice. Front Pharmacol 2022; 13:946909. [PMID: 35865942 PMCID: PMC9294457 DOI: 10.3389/fphar.2022.946909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/13/2022] [Indexed: 11/15/2022] Open
Abstract
Irritable bowel disease (IBD), which results in an elevated risk of colitis-associated colorectal cancer (CAC), is characterized by inflammation and barrier disruption of the gut. The genus Rumex has anti-oxidative and anti-inflammatory effects, and the roots of Rumex japonicus Houtt (RJ) have been traditionally used in East Asia to treat digestive problems. We investigated the protective effect of RJ against azoxymethane (AOM)-and dextran sulfate sodium (DSS)-induced CAC in C57BL/6N male mice. The mice were intraperitoneally injected with AOM on the first day and orally treated with 2% DSS for 2 weeks (on the third and sixth weeks). RJ extract (100 mg/kg) was administered to the mice in the RJ group for 4 weeks (from the third to sixth week), and all mice were sacrificed on the final day of the eighth week. Changes in morphology, tight junctions (TJs), inflammation-related factors in the colon and serum inflammatory cytokine levels were measured. The colons of AOM/DSS-treated mice were shorter and heavier than those of normal mice. The number of tumors in the colons of AOM/DSS-treated mice increased; however, RJ suppressed these changes. RJ also reduced the levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in the colon and serum, and it increased the level of IL-10 in the colon. Moreover, RJ inhibited the barrier disruption and apoptosis in the colons of AOM/DSS-treated mice. RJ effectively suppressed AOM/DSS-induced CAC by inhibiting tumor formation, inflammation, disruption of TJ, and apoptosis in the colon.
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Affiliation(s)
- Hee-Young Kim
- Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, South Korea
| | - Ji Eun Seo
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea
| | - Hanul Lee
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea
| | - Chang-Hwan Bae
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea
| | - Ki-Tae Ha
- Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, South Korea
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea
| | - Seungtae Kim
- Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, South Korea
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, South Korea
- *Correspondence: Seungtae Kim,
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40
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Wang G, Wang J, Niu C, Zhao Y, Wu P. Neutrophils: New Critical Regulators of Glioma. Front Immunol 2022; 13:927233. [PMID: 35860278 PMCID: PMC9289230 DOI: 10.3389/fimmu.2022.927233] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/06/2022] [Indexed: 11/22/2022] Open
Abstract
In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas.
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Affiliation(s)
- Guanyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinpeng Wang
- Department of Urology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoshi Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
| | - Yan Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Pengfei Wu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
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Afify SM, Hassan G, Seno A, Seno M. Cancer-inducing niche: the force of chronic inflammation. Br J Cancer 2022; 127:193-201. [PMID: 35292758 PMCID: PMC9296522 DOI: 10.1038/s41416-022-01775-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/10/2022] [Accepted: 02/22/2022] [Indexed: 12/13/2022] Open
Abstract
The growth of cancer tissue is thought to be considered driven by a small subpopulation of cells, so-called cancer stem cells (CSCs). CSCs are located at the apex of a hierarchy in a cancer tissue with self-renewal, differentiation and tumorigenic potential that produce the progeny in the tissue. Although CSCs are generally believed to play a critical role in the growth, metastasis, and recurrence of cancers, the origin of CSCs remains to be reconsidered. We hypothesise that, chronic diseases, including obesity and diabetes, establish the cancer-inducing niche (CIN) that drives the undifferentiated/progenitor cells into CSCs, which then develop malignant tumours in vivo. In this context, a CIN could be traced to chronic inflammation that involves long-lasting tissue damage and repair after being exposed to factors such as cytokines and growth factors. This must be distinguished from the cancer microenvironment, which is responsible for cancer maintenance. The concept of a CIN is most important for cancer prevention as well as cancer therapy.
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Affiliation(s)
- Said M Afify
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia, 32511, Egypt.
| | - Ghmkin Hassan
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
| | - Akimasa Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan
- Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University, Detroit, MI, USA
| | - Masaharu Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
- Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University, Detroit, MI, USA.
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Cariello M, Zerlotin R, Pasculli E, Piccinin E, Peres C, Porru E, Roda A, Gadaleta RM, Moschetta A. Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer. Cancers (Basel) 2022; 14:cancers14133081. [PMID: 35804854 PMCID: PMC9265121 DOI: 10.3390/cancers14133081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Disruption of Bile Acids (BA) regulation with increased BA concentration and modulation or their detergent pro-inflammatory activity has been linked to colorectal cancer (CRC). Farnesoid X Receptor (FXR) is the master regulator of BA homeostasis; FXR is a nuclear receptor that transcriptionally modulates their synthesis, transport and metabolism. In this study, we demonstrated that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis. Abstract The Farnesoid X Receptor (FXR) is the master regulator of Bile Acids (BA) homeostasis orchestrating their synthesis, transport and metabolism. Disruption of BA regulation has been linked to gut-liver axis diseases such as colorectal cancer (CRC). In this study, firstly we examined the role of constitutive activation of intestinal FXR in CRC; then we pre-clinically investigated the therapeutic potential of a diet enriched with a synthetic FXR agonist in two models of CRC (chemically-induced and genetic models). We demonstrated that mice with intestinal constitutive FXR activation are protected from AOM/DSS-induced CRC with a significant reduction of tumor number compared to controls. Furthermore, we evaluated the role of chemical FXR agonism in a DSS model of colitis in wild type (WT) and FXRnull mice. WT mice administered with the FXR activating diet showed less morphological alterations and decreased inflammatory infiltrates compared to controls. The FXR activating diet also protected WT mice from AOM/DSS-induced CRC by reducing tumors’ number and size. Finally, we proved that the FXR activating diet prevented spontaneous CRC in APCMin/+ mice via an FXR-dependent modulation of BA homeostasis. Our results demonstrate that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
| | - Roberta Zerlotin
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Emanuela Pasculli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Elena Piccinin
- Department of Basic Medical Science, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy;
| | - Claudia Peres
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
| | - Emanuele Porru
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy
| | - Aldo Roda
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, 40126 Bologna, Italy
| | - Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- Correspondence: (R.M.G.); (A.M.); Tel.: +39-3515833893 (R.M.G.); +39-0805593262 (A.M.)
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (M.C.); (R.Z.); (E.P.); (C.P.)
- National Institute of Biostructures and Biosystems (INBB), 00136 Rome, Italy; (E.P.); (A.R.)
- Correspondence: (R.M.G.); (A.M.); Tel.: +39-3515833893 (R.M.G.); +39-0805593262 (A.M.)
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Bartolomeu AR, Romualdo GR, Lisón CG, Besharat ZM, Corrales JAM, Chaves MÁG, Barbisan LF. Caffeine and Chlorogenic Acid Combination Attenuate Early-Stage Chemically Induced Colon Carcinogenesis in Mice: Involvement of oncomiR miR-21a-5p. Int J Mol Sci 2022; 23:ijms23116292. [PMID: 35682971 PMCID: PMC9181067 DOI: 10.3390/ijms23116292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of most common cancers worldwide, with high rates of mortality. Epidemiological findings demonstrate that coffee consumption reduces the risk of developing CRC by ~13%. In general, in vivo and in vitro findings demonstrate the antiproliferative, antioxidant and proapoptotic effects of brewed coffee or major bioavailable coffee compounds. Thus, it was assessed whether caffeine (CAF) and/or chlorogenic acid (CGA) attenuates the early-stage of chemically induced mouse colon carcinogenesis. Male Swiss mice were submitted to a 1,2-dimethylhydrazine/deoxycholic acid (DMH/DCA)-induced colon carcinogenesis model. These animals received CAF (50 mg/kg), CGA (25 mg/kg) or CAF+CGA (50 + 25 mg/kg) intragastrically for five times/week for ten weeks. CAF+CGA had the most pronounced effects on decreasing epithelial cell proliferation (Ki-67) and increasing apoptosis (cleaved caspase-3) in colonic crypts. This treatment also decreased the levels of proinflammatory cytokines IL-6, IL-17 and TNF-α, and downregulated the oncomiR miR-21a-5p in the colon. Accordingly, the analysis of miR-21a-5p targets demonstrated the genes involved in the negative regulation of proliferation and inflammation, and the positive regulation of apoptosis. Ultimately, CAF+CGA attenuated preneoplastic aberrant crypt foci (ACF) development. Our findings suggest that a combination of coffee compounds reduces early-stage colon carcinogenesis by the modulation of miR-21a-5p expression, highlighting the importance of coffee intake to prevent CRC.
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Affiliation(s)
- Ariane Rocha Bartolomeu
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (A.R.B.); (G.R.R.)
| | - Guilherme Ribeiro Romualdo
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (A.R.B.); (G.R.R.)
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
| | - Carmen Griñán Lisón
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- GENYO (Centre for Genomics and Oncological Research), Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
- UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007 Jaen, Spain
| | - Zein Mersini Besharat
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy;
| | - Juan Antonio Marchal Corrales
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- Department of Human Anatomy and Embryology, School of Medicine, University of Granada, 18016 Granada, Spain
| | - Maria Ángel García Chaves
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, 18016 Granada, Spain
| | - Luís Fernando Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
- Correspondence:
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Nagao-Kitamoto H, Kitamoto S, Kamada N. Inflammatory bowel disease and carcinogenesis. Cancer Metastasis Rev 2022; 41:301-316. [PMID: 35416564 DOI: 10.1007/s10555-022-10028-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/27/2022] [Indexed: 11/24/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer mortality worldwide. Colitis-associated colorectal cancer (CAC) is a subtype of CRC associated with inflammatory bowel disease (IBD). It is well known that individuals with IBD have a 2-3 times higher risk of developing CRC than those who do not, rendering CAC a major cause of death in this group. Although the etiology and pathogenesis of CAC are incompletely understood, animal models of chronic inflammation and human cohort data indicate that changes in the intestinal environment, including host response dysregulation and gut microbiota perturbations, may contribute to the development of CAC. Genomic alterations are a hallmark of CAC, with patterns that are distinct from those in sporadic CRC. The discovery of the biological changes that underlie the development of CAC is ongoing; however, current data suggest that chronic inflammation in IBD increases the risk of developing CAC. Therefore, a deeper understanding of the precise mechanisms by which inflammation triggers genetic alterations and disrupts intestinal homeostasis may provide insight into novel therapeutic strategies for the prevention of CAC.
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Affiliation(s)
- Hiroko Nagao-Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
| | - Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
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Supplementation with High or Low Iron Reduces Colitis Severity in an AOM/DSS Mouse Model. Nutrients 2022; 14:nu14102033. [PMID: 35631174 PMCID: PMC9147005 DOI: 10.3390/nu14102033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/03/2022] [Accepted: 05/07/2022] [Indexed: 11/17/2022] Open
Abstract
The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice’s colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1β), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.
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Ngo PA, Neurath MF, López-Posadas R. Impact of Epithelial Cell Shedding on Intestinal Homeostasis. Int J Mol Sci 2022; 23:ijms23084160. [PMID: 35456978 PMCID: PMC9027054 DOI: 10.3390/ijms23084160] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances.
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Affiliation(s)
- Phuong A. Ngo
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Correspondence:
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Ma Y, Zhang X, Yang J, Jin Y, Xu Y, Qiu J. Comprehensive Molecular Analyses of a TNF Family-Based Gene Signature as a Potentially Novel Prognostic Biomarker for Cervical Cancer. Front Oncol 2022; 12:854615. [PMID: 35392242 PMCID: PMC8980547 DOI: 10.3389/fonc.2022.854615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
Background Increasing evidence suggests that tumour necrosis factor (TNF) family genes play important roles in cervical cancer (CC). However, whether TNF family genes can be used as prognostic biomarkers of CC and the molecular mechanisms of TNF family genes remain unclear. Methods A total of 306 CC and 13 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We identified differentially expressed TNF family genes between CC and normal samples and subjected them to univariate Cox regression analysis for selecting prognostic TNF family genes. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses were performed to screen genes to establish a TNF family gene signature. Gene set enrichment analysis (GSEA) was performed to investigate the biological functions of the TNF family gene signature. Finally, methylation and copy number variation data of CC were used to analyse the potential molecular mechanisms of TNF family genes. Results A total of 26 differentially expressed TNF family genes were identified between the CC and normal samples. Next, a TNF family gene signature, including CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 was constructed based on univariate Cox, LASSO, and multivariate Cox regression analyses. The TNF family gene signature was related to age, pathological stages M and N, and could predict patient survival independently of clinical factors. Moreover, KEGG enrichment analysis suggested that the TNF family gene signature was mainly involved in the TGF-β signaling pathway, and the TNF family gene signature could affect the immunotherapy response. Finally, we confirmed that the mRNA expressions of CD27, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 were upregulated in CC, while that of EDA was downregulated. The mRNA expressions of CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 might be influenced by gene methylation and copy number variation. Conclusion Our study is the first to demonstrate that CD27, EDA, TNF, TNFRSF12A, TNFRSF13C, and TNFRSF9 might be used as prognostic biomarkers of CC and are associated with the immunotherapy response of CC.
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Affiliation(s)
- Yan Ma
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Xiaoyan Zhang
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Jiancheng Yang
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Yanping Jin
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Ying Xu
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
| | - Jianping Qiu
- Department of Gynecology and Obstetrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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Chou PH, Luo CK, Wali N, Lin WY, Ng SK, Wang CH, Zhao M, Lin SW, Yang PM, Liu PJ, Shie JJ, Wei TT. A chemical probe inhibitor targeting STAT1 restricts cancer stem cell traits and angiogenesis in colorectal cancer. J Biomed Sci 2022; 29:20. [PMID: 35313878 PMCID: PMC8939146 DOI: 10.1186/s12929-022-00803-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/14/2022] [Indexed: 01/05/2023] Open
Abstract
Background Colorectal cancer (CRC) is a worldwide cancer with rising annual incidence. New medications for patients with CRC are still needed. Recently, fluorescent chemical probes have been developed for cancer imaging and therapy. Signal transducer and activator of transcription 1 (STAT1) has complex functions in tumorigenesis and its role in CRC still needs further investigation. Methods RNA sequencing datasets in the NCBI GEO repository were analyzed to investigate the expression of STAT1 in patients with CRC. Xenograft mouse models, tail vein injection mouse models, and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were generated to study the roles of STAT1 in CRC. A ligand-based high-throughput virtual screening approach combined with SWEETLEAD chemical database analysis was used to discover new STAT1 inhibitors. A newly designed and synthesized fluorescently labeled 4’,5,7-trihydroxyisoflavone (THIF) probe (BODIPY-THIF) elucidated the mechanistic actions of STAT1 and THIF in vitro and in vivo. Colonosphere formation assay and chick chorioallantoic membrane assay were used to evaluate stemness and angiogenesis, respectively. Results Upregulation of STAT1 was observed in patients with CRC and in mouse models of AOM/DSS-induced CRC and metastatic CRC. Knockout of STAT1 in CRC cells reduced tumor growth in vivo. We then combined a high-throughput virtual screening approach and analysis of the SWEETLEAD chemical database and found that THIF, a flavonoid abundant in soybeans, was a novel STAT1 inhibitor. THIF inhibited STAT1 phosphorylation and might bind to the STAT1 SH2 domain, leading to blockade of STAT1-STAT1 dimerization. The results of in vitro and in vivo binding studies of THIF and STAT1 were validated. The pharmacological treatment with BODIPY-THIF or ablation of STAT1 via a CRISPR/Cas9-based strategy abolished stemness and angiogenesis in CRC. Oral administration of BODIPY-THIF attenuated colitis symptoms and tumor growth in the mouse model of AOM/DSS-induced CRC. Conclusions This study demonstrates that STAT1 plays an oncogenic role in CRC. BODIPY-THIF is a new chemical probe inhibitor of STAT1 that reduces stemness and angiogenesis in CRC. BODIPY-THIF can be a potential tool for CRC therapy as well as cancer cell imaging. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00803-4.
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Affiliation(s)
- Pei-Hsuan Chou
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, 1st Section, Taipei, 10051, Taiwan
| | - Cong-Kai Luo
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, 1st Section, Taipei, 10051, Taiwan
| | - Niaz Wali
- Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Taipei, 11529, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan.,Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics (TIGP-CBMB), Academia Sinica, Taipei, 11529, Taiwan
| | - Wen-Yen Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
| | - Shang-Kok Ng
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, 1st Section, Taipei, 10051, Taiwan
| | - Chun-Hao Wang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
| | - Mingtao Zhao
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, 43210, USA.,The Heart Center, Nationwide Children's Hospital, Columbus, OH, 43210, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Sheng-Wei Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan
| | - Pei-Ming Yang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Pin-Jung Liu
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan
| | - Jiun-Jie Shie
- Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Taipei, 11529, Taiwan.
| | - Tzu-Tang Wei
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, 1st Section, Taipei, 10051, Taiwan. .,Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics (TIGP-CBMB), Academia Sinica, Taipei, 11529, Taiwan.
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Assessing the Future of Solid Tumor Immunotherapy. Biomedicines 2022; 10:biomedicines10030655. [PMID: 35327456 PMCID: PMC8945484 DOI: 10.3390/biomedicines10030655] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
With the advent of cancer immunotherapy, there has been a major improvement in patient’s quality of life and survival. The growth of cancer immunotherapy has dramatically changed our understanding of the basics of cancer biology and has altered the standards of care (surgery, radiotherapy, and chemotherapy) for patients. Cancer immunotherapy has generated significant excitement with the success of chimeric antigen receptor (CAR) T cell therapy in particular. Clinical results using CAR-T for hematological malignancies have led to the approval of four CD19-targeted and one B-cell maturation antigen (BCMA)-targeted cell therapy products by the US Food and Drug Administration (FDA). Also, immune checkpoint inhibitors such as antibodies against Programmed Cell Death-1 (PD-1), Programmed Cell Death Ligand-1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) have shown promising therapeutic outcomes and long-lasting clinical effect in several tumor types and patients who are refractory to other treatments. Despite these promising results, the success of cancer immunotherapy in solid tumors has been limited due to several barriers, which include immunosuppressive tumor microenvironment (TME), inefficient trafficking, and heterogeneity of tumor antigens. This is further compounded by the high intra-tumoral pressure of solid tumors, which presents an additional challenge to successfully delivering treatments to solid tumors. In this review, we will outline and propose specific approaches that may overcome these immunological and physical barriers to improve the outcomes in solid tumor patients receiving immunotherapies.
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