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Jin B, Miao Z, Pan J, Zhang Z, Yang Y, Zhou Y, Jin Y, Niu Z, Xu Q. The emerging role of glycolysis and immune evasion in ovarian cancer. Cancer Cell Int 2025; 25:78. [PMID: 40045411 PMCID: PMC11881340 DOI: 10.1186/s12935-025-03698-x] [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: 04/26/2024] [Accepted: 02/17/2025] [Indexed: 03/09/2025] Open
Abstract
Ovarian cancer (OC) is one of the three most common malignant tumors of the female reproductive system, with the highest mortality rate among gynecologic malignancies. Like other tumors, OC cells undergo metabolic reprogramming phenomenon and convert glucose metabolism into "aerobic glycolysis" and generate a high concentration of lactate, i.e., the "Warburg effect", which provides a large amount of energy and corresponding intermediary metabolites for their survival, reproduction and metastasis. Numerous studies have shown that targeted inhibition of aerobic glycolysis and lactate metabolism is a promising strategy to enhance the sensitivity of cancer cells to immunotherapy. Therefore, this review summarizes the metabolic features of glycolysis in OC cells and highlights how abnormal lactate concentration affects the differentiation, metabolism, and function of infiltrating immune cells, which contributes to immunosuppression, and how targeted inhibition of this phenomenon may be a potential strategy to enhance the therapeutic efficacy of OC.
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Affiliation(s)
- Bowen Jin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zehua Miao
- Dalian Medical University, Dalian, China
| | - Junjie Pan
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhen Zhang
- Department of Oncology, Hangzhou Cancer Hospital, Zhejiang, Hangzhou, 310002, China
| | - Yibei Yang
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yidong Zhou
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuanxiang Jin
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zheng Niu
- Department of Gynecology, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China.
| | - Qiaoping Xu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China.
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
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Pamuk S, Ertugrul B, Kasarci G, Bireller S, Ergen A, Cakmakoglu B, Ulusan M. Focusing on tumor and it's microenvironmental immune members for head and neck cancer patients. Pathol Res Pract 2024; 263:155575. [PMID: 39236499 DOI: 10.1016/j.prp.2024.155575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/09/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
OBJECTIVE Immune-related gene expression levels in the tumor microenvironment (TM) of head and neck squamous cell carcinoma (HNSCC) patients was compared. MATERIALS AND METHODS The CD163, CD274, CD86, FUT4, FOXP3, and ITGAX levels of HNSCC patients in their tumor tissues (n =76) and surrounding tissues adjacent to the tumor (n =76) were determined using quantitative real-time PCR (qRT-PCR). Changes in these genes were also evaluated by associating with demographical data of the patients. RESULTS CD163, CD274, FUT4, and FOXP3 gene expression levels were significantly higher in tumor tissue than in surrounding tissue. FUT4 fold change was statistically higher in patients with lymph node involvement. CD86 expression was statistically lower in smokers of 50 boxes per year or more. CD163, CD274, and FUT4 expressions were increased in response to the presence of extranodal extension (ENE). CONCLUSIONS These preliminary results demonstrate the alterations in expression levels of immunologic markers are associated with the clinical presentations of HNSCC. AVAILABILITY OF DATA AND MATERIALS The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
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Affiliation(s)
- Saim Pamuk
- Department of Otorhinolaryngology & Head and Neck Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Baris Ertugrul
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Goksu Kasarci
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Graduate School of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Sinem Bireller
- Department of Biochemistry, Faculty of Pharmacy, Acibadem Mehmet Ali Aydınlar University, Istanbul, Turkey
| | - Arzu Ergen
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Bedia Cakmakoglu
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
| | - Murat Ulusan
- Department of Otorhinolaryngology & Head and Neck Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Lu N, Guo Y, Ren L, Zhao H, Yan L, Han H, Zhang S. CORO1C Regulates the Malignant Biological Behavior of Ovarian Cancer Cells and Modulates the mRNA Expression Profile through the PI3K/AKT Signaling Pathway. Cell Biochem Biophys 2024:10.1007/s12013-024-01591-4. [PMID: 39433598 DOI: 10.1007/s12013-024-01591-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2024] [Indexed: 10/23/2024]
Abstract
Ovarian cancer (OC) is a frequently occurring gynecological tumor, and its global incidence has recently increased. Coronin-like actin-binding protein 1C (CORO1C) is known to activate the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway and promote tumor progression. However, its role in OC remains unclear. This study investigated the role of CORO1C in OC malignancy. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine AKT and CORO1C mRNA expression in clinical OC tissues and cells. Immunohistochemical analysis and western blotting were used to examine protein expression in OC tissues and cells, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), scratch wound-healing, and Transwell assays were performed to examine cell proliferation and migration. RNA-Seq was used to validate the relationship between AKT and CORO1C expression. The results showed that CORO1C was highly expressed in clinical OC tissues and SKOV3 cells, correlating with the International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, CORO1C knockout inhibited the proliferation, migration, and invasion of SKOV3 cells; altered the gene expression patterns in these cells; and was closely associated with the PI3K/AKT pathway. Western blotting confirmed that CORO1C knockout reduced the levels of phosphorylated PI3K and AKT. Additionally, CORO1C knockout increased phosphatase and tensin homologs deleted on chromosome 10 (PTEN) protein expression, whereas CORO1C overexpression decreased it. In conclusion, this study demonstrated that high CORO1C levels in OC are associated with greater metastasis and worse prognosis. CORO1C negatively regulates PTEN expression, activates the PI3K/AKT pathway, and promotes OC cell malignancy In patients with OC, CORO1C may function as an effective therapeutic and predictive biomarker.
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Affiliation(s)
- Na Lu
- Gynecology and oncology department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Yongfeng Guo
- Gynecology and oncology department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Lixin Ren
- General surgery department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Hongwei Zhao
- Gynecology and oncology department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Lijun Yan
- Gynecology and oncology department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Haiqiong Han
- Gynecology and oncology department, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, China
| | - Sanyuan Zhang
- Department of gynecology and obstetrics, The First Clinical Medical College of Shanxi Medical University, Taiyuan, 030000, China.
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Setayesh T, Hu Y, Vaziri F, Wei D, Wan YJY. The spatial impact of a Western diet in enriching Galectin-1-regulated Rho, ECM, and SASP signaling in a novel MASH-HCC mouse model. Biomark Res 2024; 12:122. [PMID: 39402682 PMCID: PMC11476289 DOI: 10.1186/s40364-024-00660-3] [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: 08/14/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) arising from metabolic dysfunction-associated steatohepatitis (MASH) presents a significant clinical challenge, particularly given the prevalence of the Western diet (WD). The influence of diet on the tumor microenvironment remains poorly understood. Galectin-1 (Gal-1) is a biomarker for HCC and has a crucial role in liver carcinogenesis. Our previous studies demonstrated that silencing Gal-1 effectively treats mouse HCC. However, the impacts of a WD on Gal-1 signaling on MASH to HCC progression are unknown, and this study addresses these knowledge gaps. METHODS We developed a novel MASH-HCC mouse model. Using spatial transcriptomics and multiplex immunohistochemistry (IHC), we studied the effects of a WD on the liver and tumor microenvironment. By modulating Gal-1 expression through silencing and overexpression, we explored the location-specific impacts of WD on Gal-1 signaling. RESULTS Pathways such as Rho signaling, extracellular matrix (ECM) remodeling, and senescence-associated secretory phenotypes (SASP) were prominently activated in WD-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH-HCC, compared to healthy livers controls. Furthermore, Rho GTPase effectors, ECM remodeling, neutrophil degranulation, cellular stress, and cell cycle pathways were consistently enriched in human and mouse MASH-HCC. Spatially, these pathways were enriched in the tumor and tumor margins of mouse MASH-HCC. Additionally, there was a notable increase in CD11c and PD-L1-positive cells from non-tumor tissues to the tumor margin and inside the tumor of MASH-HCC, suggesting compromised immune surveillance due to WD intake. Moreover, MASH-HCC exhibited significant Gal-1 induction in N-Cadherin-positive cells, indicating enhanced epithelial-to-mesenchymal transition (EMT). Modulating Gal-1 expression in MASH-HCC further established its specific roles in regulating Rho signaling and SASP in the tumor margin and non-tumor tissues in MASH-HCC. CONCLUSION WD intake significantly influences vital cellular processes involved in Gal-1-mediated signaling, including Rho signaling and ECM remodeling, in the tumor microenvironment, thereby contributing to the development of MASH-HCC.
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Affiliation(s)
- Tahereh Setayesh
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Ying Hu
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Farzam Vaziri
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Dongguang Wei
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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Yang B, Shan C, Song X, Lv X, Long Y, Zeng D, An R, Lan X, Gai Y. Development and evaluation of albumin binder-conjugated heterodimeric radiopharmaceuticals targeting integrin α vβ 3 and CD13 for cancer therapy. Eur J Nucl Med Mol Imaging 2024; 51:3334-3345. [PMID: 38787395 DOI: 10.1007/s00259-024-06766-y] [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: 02/27/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [68Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvβ3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate. METHODS New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5-6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177Lu for small-animal SPECT/CT and ex vivo biodistribution investigation. RESULTS We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [68Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [68Ga]Ga-L0 without an albumin binder. [68Ga]Ga-L6 outperformed [68Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [177Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications. CONCLUSION A new integrin αvβ3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177Lu.
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Affiliation(s)
- Biao Yang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
| | - Changyu Shan
- Hexin (Suzhou) Pharmaceutical Technology Co., Ltd, Taicang City, 215421, China
| | - Xiangming Song
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
| | - Xiaoying Lv
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
| | - Yu Long
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China
| | - Dexing Zeng
- Hexin (Suzhou) Pharmaceutical Technology Co., Ltd, Taicang City, 215421, China
| | - Rui An
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China.
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China.
| | - Yongkang Gai
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan, 430022, China.
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Han X, Liu Z, Cui M, Lin J, Li Y, Qin H, Sheng J, Zhang X. FGA influences invasion and metastasis of hepatocellular carcinoma through the PI3K/AKT pathway. Aging (Albany NY) 2024; 16:12806-12819. [PMID: 39227068 PMCID: PMC11501378 DOI: 10.18632/aging.206011] [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: 11/17/2023] [Accepted: 06/03/2024] [Indexed: 09/05/2024]
Abstract
Fibrinogen is an important plasma protein composed of three polypeptide chains, fibrinogen alpha (FGA), beta, and gamma. Apart from being an inflammation regulator, fibrinogen also plays a role in tumor progression. Liver cancer usually has a poor prognosis, with chronic hepatitis being the main cause of liver cirrhosis and hepatocellular carcinoma (HCC). FGA serves as a serological marker for chronic hepatitis, but its relationship with liver cancer remains unclear. Through bioinformatics analysis and agarose gel electrophoresis, we found that FGA was downregulated in HCC and correlated with tumor stage and grade. By constructing both FGA gene knockout and overexpression cell models, we demonstrated that overexpressing FGA inhibited migration and invasion of liver cancer cells through Transwell migration/invasion and wound healing assays. Western blotting experiments showed that FGA overexpression increased the expression of the epithelial-mesenchymal transition marker protein E-cadherin while decreasing N-cadherin and slug protein expression. In addition, FGA knockout activated the PI3K/AKT pathway. In a mouse model of metastatic tumors, overexpression of FGA restricted the spread of tumor cells. In conclusion, FGA exhibits an inhibitory effect on tumor metastasis, providing new insights for the treatment of advanced HCC metastatic tumors.
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Affiliation(s)
- Xi Han
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Zefeng Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Jie Lin
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Yongzhi Li
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Hanjiao Qin
- Department of Radiotherapy, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
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Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, Kazeminejad A. VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives. Life Sci 2024; 345:122563. [PMID: 38508233 DOI: 10.1016/j.lfs.2024.122563] [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: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Armaghan Kazeminejad
- Department of Dermatology, Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences,Sari, Iran
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Alblihy A. From desert flora to cancer therapy: systematic exploration of multi-pathway mechanisms using network pharmacology and molecular modeling approaches. Front Pharmacol 2024; 15:1345415. [PMID: 38666020 PMCID: PMC11043532 DOI: 10.3389/fphar.2024.1345415] [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: 11/27/2023] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Ovarian cancer, often labeled a "silent killer," remains one of the most compelling and challenging areas of cancer research. In 2019 alone, a staggering 222,240 new cases of ovarian cancer were reported, with nearly 14,170 lives tragically lost to this relentless disease. The absence of effective diagnostic methods, increased resistance to chemotherapy, and the heterogeneous nature of ovarian cancer collectively contribute to the unfavorable prognosis observed in the majority of cases. Thus, there is a pressing need to explore therapeutic interventions that offer superior efficacy and safety, thereby enhancing the survival prospects for ovarian cancer patients. Recognizing this potential, our research synergizes bioinformatics with a network pharmacology approach to investigate the underlying molecular interactions of Saudi Arabian flora (Onopordum heteracanthum, Acacia ehrenbergiana, Osteospermum vaillantii, Cyperus rotundus, Carissa carandas, Carissa spinarum, and Camellia sinensis) in ovarian cancer treatment. At first, phytoconstituents of indigenous flora and their associated gene targets, particularly those pertinent to ovarian cancer, were obtained from open-access databases. Later, the shared targets of plants and diseases were compared to identify common targets. A protein-protein interaction (PPI) network of predicted targets was then constructed for the identification of key genes having the highest degree of connectivity among networks. Following that, a compound-target protein-pathway network was constructed, which uncovered that, namely, hispidulin, stigmasterol, ascorbic acid, octopamine, cyperene, kaempferol, pungenin, citric acid, d-tartaric acid, beta-sitosterol, (-)-epicatechin gallate, and (+)-catechin demonstrably influence cell proliferation and growth by impacting the AKT1 and VEGFA proteins. Molecular docking, complemented by a 20-ns molecular dynamic (MD) simulation, was used, and the binding affinity of the compound was further validated. Molecular docking, complemented by a 20-ns MD simulation, confirmed the binding affinity of these compounds. Specifically, for AKT1, ascorbic acid showed a docking score of -11.1227 kcal/mol, interacting with residues Ser A:240, Leu A:239, Arg A:243, Arg C:2, and Glu A:341. For VEGFA, hispidulin exhibited a docking score of -17.3714 kcal/mol, interacting with Asn A:158, Val A:190, Gln B:160, Ser A:179, and Ser B:176. To sum up, both a theoretical and empirical framework were established by this study, directing more comprehensive research and laying out a roadmap for the potential utilization of active compounds in the formulation of anti-cancer treatments.
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Affiliation(s)
- Adel Alblihy
- Medical Center, King Fahad Security College (KFSC), Riyadh, Saudi Arabia
- Department of Criminal Justice and Forensic Sciences, King Fahad Security Collage, Riyadh, Saudi Arabia
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9
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Meng Q, Han J, Wang P, Jia C, Guan M, Zhang B, Zhao W. BMS-794833 reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. J Bone Oncol 2024; 45:100594. [PMID: 38532893 PMCID: PMC10963651 DOI: 10.1016/j.jbo.2024.100594] [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: 11/21/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Background Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small-molecule multi-target tyrosine kinase inhibitor (TKI), is the first-line drug in treating osteosarcoma, especially in late-stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET). Therefore, the identification of new TKI warrants further investigation. Methods We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Results Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial-mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo. Conclusion Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.
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Affiliation(s)
- Qingtao Meng
- Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, Dalian 116028, China
- Department of Orthopedics, Dalian NO.3 People’s Hospital, Dalian 116091, China
| | - Jian Han
- Department of Orthopedics, Dalian NO.3 People’s Hospital, Dalian 116091, China
| | - Peng Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chenxu Jia
- Department of Orthopedics, Dalian NO.3 People’s Hospital, Dalian 116091, China
| | - Mingyang Guan
- Department of Orthopedics, Dalian NO.3 People’s Hospital, Dalian 116091, China
| | - Bolun Zhang
- Department of Orthopedics, Dalian NO.3 People’s Hospital, Dalian 116091, China
| | - Wenzhi Zhao
- Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, Dalian 116028, China
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Wang Y, Wang R, Zhu J, Chen L. Identification of mitophagy and ferroptosis-related hub genes associated with intracerebral haemorrhage through bioinformatics analysis. Ann Hum Biol 2024; 51:2334719. [PMID: 38863372 DOI: 10.1080/03014460.2024.2334719] [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: 11/07/2023] [Accepted: 03/21/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Mitophagy and ferroptosis occur in intracerebral haemorrhage (ICH) but our understanding of mitophagy and ferroptosis-related genes remains incomplete. AIM This study aims to identify shared ICH genes for both processes. METHODS ICH differentially expressed mitophagy and ferroptosis-related genes (DEMFRGs) were sourced from the GEO database and literature. Enrichment analysis elucidated functions. Hub genes were selected via STRING, MCODE, and MCC algorithms in Cytoscape. miRNAs targeting hubs were predicted using miRWalk 3.0, forming a miRNA-hub gene network. Immune microenvironment variances were assessed with MCP and TIMER. Potential small molecules for ICH were forecasted via CMap database. RESULTS 64 DEMFRGs and ten hub genes potentially involved in various processes like ferroptosis, TNF signalling pathway, MAPK signalling pathway, and NF-kappa B signalling pathway were discovered. Several miRNAs were identified as shared targets of hub genes. The ICH group showed increased infiltration of monocytic lineage and myeloid dendritic cells compared to the Healthy group. Ten potential small molecule drugs (e.g. Zebularine, TWS-119, CG-930) were predicted via CMap. CONCLUSION Several shared genes between mitophagy and ferroptosis potentially drive ICH progression via TNF, MAPK, and NF-kappa B pathways. These results offer valuable insights for further exploring the connection between mitophagy, ferroptosis, and ICH.
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Affiliation(s)
- Yan Wang
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Rufeng Wang
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Jianzhong Zhu
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Ling Chen
- Department of Gynaecology, People's Hospital Affiliated to Cangzhou Medical College, Cangzhou, China
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11
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Shen L, Huang H, Wei Z, Chen W, Li J, Yao Y, Zhou J, Liu J, Sun S, Xia W, Zhang T, Yu X, Shen J, Wang W, Jiang J, Huang J, Jiang M, Ni C. Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer. MedComm (Beijing) 2023; 4:e433. [PMID: 38053815 PMCID: PMC10694390 DOI: 10.1002/mco2.433] [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: 04/17/2023] [Revised: 11/11/2023] [Accepted: 11/12/2023] [Indexed: 12/07/2023] Open
Abstract
Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.
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Affiliation(s)
- Lesang Shen
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Huanhuan Huang
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Zichen Wei
- Center for Genetic MedicineThe Fourth Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
- Department of AnesthesiologyTaihe HospitalHubei University of MedicineShiyanChina
| | - Wuzhen Chen
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Jiaxin Li
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Yao Yao
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Jun Zhou
- Department of Breast SurgeryAffiliated Hangzhou First People's HospitalZhejiang UniversityHangzhouChina
| | - Jian Liu
- Department of Breast SurgeryAffiliated Hangzhou First People's HospitalZhejiang UniversityHangzhouChina
| | - Shanshan Sun
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Wenjie Xia
- Department of Breast SurgeryZhejiang Provincial People's HospitalHangzhouChina
| | - Ting Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
- Department of Radiation OncologySecond Affiliated HospitalZhejiang UniversityHangzhouChina
| | - Xiuyan Yu
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Jun Shen
- Department of Surgical OncologySir Run Run Shaw Hospital, Zhejiang UniversityHangzhouChina
| | - Weilan Wang
- Department of Breast SurgeryChangxing People's HospitalHuzhouChina
| | - Jingxin Jiang
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Jian Huang
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Ming Jiang
- Center for Genetic MedicineThe Fourth Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
- Zhejiang Provincial Key Laboratory of Genetic and Developmental DisordersHangzhouChina
| | - Chao Ni
- Department of Breast SurgerySecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang ProvinceSecond Affiliated Hospital, Zhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
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12
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Mannan A, Dhiamn S, Garg N, Singh TG. Pharmacological modulation of Sonic Hedgehog signaling pathways in Angiogenesis: A mechanistic perspective. Dev Biol 2023; 504:58-74. [PMID: 37739118 DOI: 10.1016/j.ydbio.2023.09.009] [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: 06/01/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
The Sonic hedgehog (SHh) signaling pathway is an imperative operating network that helps in regulates the critical events during the development processes like multicellular embryo growth and patterning. Disruptions in SHh pathway regulation can have severe consequences, including congenital disabilities, stem cell renewal, tissue regeneration, and cancer/tumor growth. Activation of the SHh signal occurs when SHh binds to the receptor complex of Patch (Ptc)-mediated Smoothened (Smo) (Ptc-smo), initiating downstream signaling. This review explores how pharmacological modulation of the SHh pathway affects angiogenesis through canonical and non-canonical pathways. The canonical pathway for angiogenesis involves the activation of angiogenic cytokines such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), stromal cell-derived factor 1α, transforming growth factor-β1 (TGF-β1), and angiopoietins (Ang-1 and Ang-2), which facilitate the process of angiogenesis. The Non-canonical pathway includes indirect activation of certain pathways like iNOS/Netrin-1/PKC, RhoA/Rock, ERK/MAPK, PI3K/Akt, Wnt/β-catenin, Notch signaling pathway, and so on. This review will provide a better grasp of the mechanistic approach of SHh in mediating angiogenesis, which can aid in the suppression of certain cancer and tumor growths.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiamn
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Nikhil Garg
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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Yang J, Liu Y, Dong M. Integrated Bioinformatics Analysis to Screen Hub Gene Signatures for Fetal Growth Restriction. Genet Res (Camb) 2023; 2023:3367406. [PMID: 37033160 PMCID: PMC10079385 DOI: 10.1155/2023/3367406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/26/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
Background. Fetal growth restriction (FGR) is the impairment of the biological growth potential of the fetus and often leads to adverse pregnancy outcomes. The molecular mechanisms for the development of FGR, however, are still unclear. The purpose of this study is to identify critical genes associated with FGR through an integrated bioinformatics approach and explore the potential pathogenesis of FGR. Methods. We downloaded FGR-related gene microarray data, used weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs), and protein-protein interaction (PPI) networks to screen hub genes. The GSE24129 gene set was used for validation of critical gene expression levels and diagnostic capabilities. Results. A weighted gene co-expression network was constructed, and 5000 genes were divided into 12 modules. Of these modules, the blue module showed the closest relationship with FGR. Taking the intersection of the DEGs and genes in the blue module as pivotal genes, 277 genes were identified, and 20 crucial genes were screened from the PPI network. The GSE24129 gene set verified the expression of 20 genes, and CXCL9, CXCR3, and ITGAX genes were identified as actual pivotal genes. The expression levels of CXCL9, CXCR3, and ITGAX were increased in both the training and validation sets, and ROC curve validation revealed that these three pivotal genes had a significant diagnostic ability for FGR. Single-gene GSEA results showed that all three core genes activated “hematopoietic cell lineage” and “cell adhesion molecules” and inhibited the “cGMP-PKG signaling pathway” in the development of FGR. CXCL9, CXCR3, and ITGAX may therefore be closely associated with the development of FGR and may serve as potential biomarkers for the diagnosis and treatment of FGR.
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14
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Wang X, Guan Z, Tang W, Wang X, Xu C, Shan E, Wang W, Gao Y. PAX5/ITGAX Contributed to the Progression of Atherosclerosis by Regulation of B Differentiation via TNF-α Signaling Pathway. DNA Cell Biol 2023; 42:97-104. [PMID: 36730754 DOI: 10.1089/dna.2022.0461] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
To investigate the effect of paired box protein 5 (PAX5)/integrin subunit alpha X (ITGAX) in atherosclerosis (AS). AS model was established using ApoE-/- mice (C57BL/6). Human vascular smooth muscle cells (HVSMCs) were stimulated with ox-LDL. Quantitative reverse transcription polymerase chain reaction and Western blotting were used to detect the expression levels of genes and proteins. Reporter constructs and luciferase assays were used to investigate the role of ITGAX and PAX5. Cells proliferation and inflammation factors were detected. The results presented that aortic plaque area, lipid content, serum triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels were significantly increased in the high-fat diet group (p < 0.05). ITGAX was upregulated in atherosclerotic tissues. In addition, ox-LDL treatment induced HVSMCs proliferation, migration, and invasion. Reporter constructs and luciferase assays indicated ITGAX interaction with PAX5. Furthermore, siITGAX and siPAX5 cotransfection restored the rate of HVSMCs in G1 and S and G2/M phases, decreased the content of tumor necrosis factor-alpha (TNF-ɑ), interleukin (IL)-6, and IL-8 (p < 0.05). Interestingly, siITGAX and siPAX5 cotransfection also decreased the expression levels of TNF-α, TNF-R1, TNF-R2, CD19, and CD86 (p < 0.05). Our results suggest that ITGAX may be a potential therapeutic target for AS.
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Affiliation(s)
- Xiangkui Wang
- The First Clinical College of Jinan University, Jinan University, Guangzhou, China
- Department of Vascular Surgery, Huaibei General Miner Hospital, Huaibei, China
| | - Zeyu Guan
- Department of Vascular Surgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Wenbo Tang
- Department of Vascular Surgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaogao Wang
- Department of Vascular Surgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Chao Xu
- Department of Vascular Surgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Erbo Shan
- Department of Vascular Surgery and the Second Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Wei Wang
- Department of Surgical Oncology, the Second Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yong Gao
- The First Clinical College of Jinan University, Jinan University, Guangzhou, China
- Department of Vascular Surgery, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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15
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Ni L, Li P, Li M, Huang S, Dang N. SERPINB8 and furin regulate ITGAX expression and affect the proliferation and invasion of melanoma cells. Exp Dermatol 2023; 32:24-29. [PMID: 36134483 DOI: 10.1111/exd.14677] [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: 04/07/2022] [Revised: 09/14/2022] [Accepted: 09/18/2022] [Indexed: 01/12/2023]
Abstract
In the past 10 years, the systemic treatment of advanced melanoma has undergone tremendous changes through the development of targeted therapy. However, there is still a long way to go. This study aims to characterize the function and interaction of ITGAX, SERPINB8 and furin in BRAF V600E mutant melanoma. Differentially expressed genes related to BRAF V600E mutation and BRAFi treatment were obtained by analysing GSE141484 and GSE22838. two kinds of BRAFi (Vemurafenib, 10 μM; Dabrafenib, 1 μM) were used to treat A375 and 1205Lu cells, respectively. The expression of ITGAX, SERPINB8 and Furin in A375 and 1205Lu cells was down-regulated by specific siRNAs, and cell proliferation, clone formation and invasion were detected by CCK-8, colony formation and transwell assays. The physical binding of furin and SERPINB8 was detected by immunoprecipitation. BRAFi treatment down-regulated the ITGAX and SERPINB8 expression and did not change furin expression. Knockdown of ITGAX and SERPINB8 both inhibited the proliferation and invasion of A375 and 1205Lu cells. Knocking down SERPINB8 down-regulated the expression of ITGAX. Furin knockdown and inhibitors all up-regulated the protein level of ITGAX. SERPINB8 can physically bind to furin. In summary, SERPINB8 and furin regulate the expression of ITGAX in melanoma cells, and ITGAX significantly promotes the proliferation and invasion of melanoma cells.
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Affiliation(s)
- Li Ni
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Pin Li
- Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Mingming Li
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shuhong Huang
- Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Ningning Dang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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16
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Chang C, Cai R, Wu Q, Su Q. Uncovering the Genetic Link between Acute Myocardial Infarction and Ulcerative Colitis Co-Morbidity through a Systems Biology Approach. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2023; 8. [DOI: 10.15212/cvia.2023.0034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Background: Cardiovascular diseases, particularly acute myocardial infarction, are the leading cause of disability and death. Atherosclerosis, the pathological basis of AMI, can be accelerated by chronic inflammation. Ulcerative colitis (UC), a chronic inflammatory disease associated with immunity, contributes to the risk of AMI development. However, controversy continues to surround the relationship between these two diseases. The present study unravels the pathogenesis of AMI and UC, to provide a new perspective on the clinical management of patients with these comorbidities.
Methods: Microarray datasets GSE66360 and GSE87473 were downloaded from the Gene Expression Omnibus database. Common differentially expressed genes (co-DEGs) between AMI and UC were identified, and the following analyses were performed: enrichment analysis, protein-protein interaction network construction, hub gene identification and co-expression analysis.
Results: A total of 267 co-DEGs (233 upregulated and 34 downregulated) were screened for further analysis. GO enrichment analysis suggested important roles of chemokines and cytokines in AMI and UC. In addition, the lipopolysaccharide-mediated signaling pathway was found to be closely associated with both diseases. KEGG enrichment analysis revealed that lipid and atherosclerosis, NF-κB, TNF and IL-17 signaling pathways are the core mechanisms involved in the progression of both diseases. Finally, 11 hub genes were identified with cytoHubba: TNF, IL1B, TLR2, CXCL8, STAT3, MMP9, ITGAX, CCL4, CSF1R, ICAM1 and CXCL1.
Conclusion: This study reveals a co-pathogenesis mechanism of AMI and UC regulated by specific hub genes, thus providing ideas for further mechanistic studies, and new perspectives on the clinical management of patients with these comorbidities.
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Perossi IFS, Saito MM, Varallo GR, de Godoy BLV, Colombo J, Zuccari DAPC. Protein Expression of PI3K/AKT/mTOR Pathway Targets Validated by Gene Expression and its Correlation with Prognosis in Canine Mammary Cancer. J Mammary Gland Biol Neoplasia 2022; 27:241-252. [PMID: 36323932 DOI: 10.1007/s10911-022-09527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 12/31/2022] Open
Abstract
Mammary cancer is the main type of neoplasia in female dogs and is considered an adequate model for the biological and therapeutic study of cancer in women. The PIK3CA/AKT/mTOR pathway plays a central role in cellular homeostasis and is often dysregulated in cancer. The increased expression of PI3K protein in the literature is associated with a poor prognosis, and alterations in the PIK3CA gene can lead to changes in downstream pathways. Thus, the objective of this study was to validate the protein expression to confirm the gene expression of proteins belonging to the main pathway PI3K and PTEN, and their downstream pathways through ZEB1, ZEB2, HIF1A, VHL, CASP3 and PARP1 relating to prognosis in canine mammary cancer. For protein studies, the samples came from 58 female dogs with mammary neoplasia, immunohistochemistry was performed and its analysis by the histoscore method. For the genetic evaluation, the samples came from 13 patients, the DNA was extracted and the analysis for quantitative expression. Through immunohistochemistry, PI3K positivity was significantly associated with affected regional lymph node, distant metastasis, patients with HER2+, Triple Negative and Luminal B phenotypes, and the lowest survival rates. Through gene expression, we observed higher gene expression of ZEB2 and PARP1 both among patients who were alive and who died, which was not true for the expressions of PIK3CA and HIF1A. In conclusion, the data observed in this work are promising in the study of new molecular prognostic markers such as PI3K, ZEB2 and PARP1 for canine mammary cancer.
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Affiliation(s)
- Isabela F S Perossi
- Instituto de Biociências, Letras e Ciências Exatas (IBILCE) UNESP, São José do Rio Preto, Brazil.
| | - Mylena M Saito
- Centro Universitário de Rio Preto (UNIRP), São José do Rio Preto, Brazil
| | | | | | - Jucimara Colombo
- Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, Brazil
| | - Debora A P C Zuccari
- Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, Brazil
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Cruz-García EM, Frigolet ME, Canizales-Quinteros S, Gutiérrez-Aguilar R. Differential Gene Expression of Subcutaneous Adipose Tissue among Lean, Obese, and after RYGB (Different Timepoints): Systematic Review and Analysis. Nutrients 2022; 14:nu14224925. [PMID: 36432612 PMCID: PMC9693162 DOI: 10.3390/nu14224925] [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: 09/14/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/23/2022] Open
Abstract
The main roles of adipose tissue include triglycerides storage and adipokine secretion, which regulate energy balance and inflammation status. In obesity, adipocyte dysfunction leads to proinflammatory cytokine production and insulin resistance. Bariatric surgery is the most effective treatment for obesity, the gold-standard technique being Roux-en-Y gastric bypass (RYGB). Since metabolic improvements after RYGB are clear, a better understanding of adipose tissue molecular modifications could be derived from this study. Thus, the aim of this systematic review was to find differentially expressed genes in subcutaneous adipose tissue of lean, obese and post-RYGB (distinct timepoints). To address this objective, publications from 2015-2022 reporting gene expression (candidate genes or transcriptomic approach) of subcutaneous adipose tissue from lean and obese individuals before and after RGYB were searched in PubMed, Elsevier, and Springer Link. Excluded publications were reviews, studies analyzing serum, other types of tissues, or bariatric procedures. A risk-of-bias summary was created for each paper using Robvis, to finally include 17 studies. Differentially expressed genes in post-RYGB vs. obese and lean vs. obese were obtained and the intersection among these groups was used for analysis and gene classification by metabolic pathway. Results showed that the lean state as well as the post-RYGB is similar in terms of increased expression of insulin-sensitizing molecules, inducing lipogenesis over lipolysis and downregulating leukocyte activation, cytokine production and other factors that promote inflammation. Thus, massive weight loss and metabolic improvements after RYGB are accompanied by gene expression modifications reverting the "adipocyte dysfunction" phenomenon observed in obesity conditions.
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Affiliation(s)
- Elena Marisol Cruz-García
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
| | - María E. Frigolet
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genόmica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genόmica (INMEGEN), Mexico City 14610, Mexico
| | - Ruth Gutiérrez-Aguilar
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
- División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
- Correspondence: ; Tel.: +52-5552289917 (ext. 4509)
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Ghoneum A, Gonzalez D, Afify H, Shu J, Hegarty A, Adisa J, Kelly M, Lentz S, Salsbury F, Said N. Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway. Cancers (Basel) 2022; 14:5099. [PMID: 36291886 PMCID: PMC9600774 DOI: 10.3390/cancers14205099] [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: 09/09/2022] [Revised: 10/03/2022] [Accepted: 10/13/2022] [Indexed: 12/04/2022] Open
Abstract
Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.
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Affiliation(s)
- Alia Ghoneum
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Daniela Gonzalez
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Hesham Afify
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Junjun Shu
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Abigail Hegarty
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Jemima Adisa
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Michael Kelly
- Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
- Comprehensive Cancer Center, Wake Forest Baptist Health Sciences, Winston Salem, NC 27157, USA
| | - Samuel Lentz
- Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
- Comprehensive Cancer Center, Wake Forest Baptist Health Sciences, Winston Salem, NC 27157, USA
- Departments of Urology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
| | - Freddie Salsbury
- Comprehensive Cancer Center, Wake Forest Baptist Health Sciences, Winston Salem, NC 27157, USA
- Department of Physics, Wake Forest University, Winston Salem, NC 27109, USA
| | - Neveen Said
- Departments of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
- Comprehensive Cancer Center, Wake Forest Baptist Health Sciences, Winston Salem, NC 27157, USA
- Departments of Urology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
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20
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Wang Y, Zhang Y, Li Y, Liu Y, Liu Y. Signature of gene expression profile of liver sinusoidal endothelial cells in nonalcoholic steatohepatitis. Front Cell Dev Biol 2022; 10:946566. [PMID: 36211451 PMCID: PMC9533023 DOI: 10.3389/fcell.2022.946566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
Background: There has been emerging evidence that liver sinusoidal endothelial cells (LSECs) play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aims to figure out the signature of the gene expression profile of LSECs in NASH and to explore potential biomarkers related to damaged LSECs in NASH.Methods and materials: Animal experiments were performed to demonstrate the significant structural damage of LSECs in the NASH model. To further understand the functional changes of these damaged LSECs in NASH, we used the public GEO database that contained microarray data for the gene expression of LSECs in NASH and normal mouse liver. Differentially expressed genes (DEGs) were analyzed, and further Gene Ontology (GO) enrichment analysis was performed to understand the functional changes. The hub genes were then identified and validated via external GEO databases.Results: There was significant structural damage to LSECs in the NASH model, accompanied by remarkable functional changes of LSECs with 174 DEGs (156 upregulated and 18 downregulated genes). The functions of these DEGs were mainly enriched in the inflammatory reactions and immune responses. Nine specifically expressed hub genes were identified. Among them, CCL4 and ITGAX showed the most significant correlation with NASH, with AUROC of 0.77 and 0.86, respectively. The protein–protein interaction network, mRNA–miRNA interaction network, and ceRNA network were further predicted.Conclusion: LSECs show significant structural damage and functional changes in NASH. The LSEC-related DEGs, such as CCL4 and ITGAX, might be promising biomarkers as well as potential treatment targets for NASH.
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Affiliation(s)
- Yang Wang
- Department of Gastroenterology, Peking University People’s Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing, China
- *Correspondence: Yang Wang, ; Yulan Liu,
| | - Yifan Zhang
- Department of Gastroenterology, Peking University People’s Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing, China
| | - Yimin Li
- Department of Rheumatology and Immunology, Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis, Peking University People’s Hospital, Beijing, China
| | - Yun Liu
- Department of Gastroenterology, Peking University People’s Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People’s Hospital, Beijing, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People’s Hospital, Beijing, China
- *Correspondence: Yang Wang, ; Yulan Liu,
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21
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Liu Y, Liu H, Sheng B, Pan S, Wang ZW, Zhu X. The functions of lncRNAs in the HPV-negative cervical cancer compared with HPV-positive cervical cancer. Apoptosis 2022; 27:685-696. [PMID: 35980559 DOI: 10.1007/s10495-022-01761-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2022] [Indexed: 12/24/2022]
Abstract
Cervical cancer is one of the most common female malignancies. Human papillomaviruses (HPV) are the main causative agents of virtually all cervical carcinomas. Nevertheless, emerging evidence has demonstrated that a small proportion of cervical cancer patients are HPV negative. Long noncoding RNAs (lncRNAs) have been identified to play a crucial role in cervical cancer development. Here, this review describes the incidence and development of HPV-negative cervical cancer. Moreover, HPV-negative cervical cancers are more likely diagnosed at non-squamous type, older ages, more advanced stage and metastases, and associated with poorer prognosis as compared to HPV-positive cervical cancer. Furthermore, the significant role and functions of lncRNAs underlying HPV-negative cervical cancer is clarified.
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Affiliation(s)
- Yi Liu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Hejing Liu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Bo Sheng
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Shuya Pan
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Zhi-Wei Wang
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
| | - Xueqiong Zhu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
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22
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Kia ZA, Sadati Bizaki ST, Ghareh Tapeh EA, Harijani SM, Katal N, Baziary RG. Recovering the angiogenic/angiostatic balance in NNK-induced lung carcinoma via 12 weeks of submaximal swimming and Nigella sativa nanocapsule. Toxicol Rep 2022; 9:1452-1460. [DOI: 10.1016/j.toxrep.2022.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 10/17/2022] Open
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23
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The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol 2022; 127:104787. [DOI: 10.1016/j.yexmp.2022.104787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/15/2022] [Accepted: 05/21/2022] [Indexed: 01/02/2023]
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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25
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Comparative Transcriptomic Analysis of Regenerated Skins Provides Insights into Cutaneous Air-Breathing Formation in Fish. BIOLOGY 2021; 10:biology10121294. [PMID: 34943209 PMCID: PMC8698756 DOI: 10.3390/biology10121294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022]
Abstract
Cutaneous air-breathing is one of the air-breathing patterns in bimodal respiration fishes, while little is known about its underlying formation mechanisms. Here, we first investigated the skin regeneration of loach (Misgurnus anguillicaudatus, a cutaneous air-breathing fish) and yellow catfish (Pelteobagrus fulvidraco, a water-breathing fish) through morphological and histological observations. Then, the original skins (OS: MOS, POS) and regenerated skins (RS: MRS, PRS) when their capillaries were the most abundant (the structural foundation of air-breathing in fish) during healing, of the two fish species were collected for high-throughput RNA-seq. A total of 56,054 unigenes and 53,731 unigenes were assembled in loach and yellow catfish, respectively. A total of 640 (460 up- and 180 down-regulated) and 4446 (2340 up- and 2106 down-regulated) differentially expressed genes (DEGs) were respectively observed in RS/OS of loach and yellow catfish. Subsequently, the two DEG datasets were clustered in GO, KOG and KEGG databases, and further analyzed by comparison and screening. Consequently, tens of genes and thirteen key pathways were targeted, indicating that these genes and pathways had strong ties to cutaneous skin air-breathing in loach. This study provides new insights into the formation mechanism of cutaneous air-breathing and also offers a substantial contribution to the gene expression profiles of skin regeneration in fish.
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26
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Identification of early diagnostic biomarkers via WGCNA in gastric cancer. Biomed Pharmacother 2021; 145:112477. [PMID: 34864309 DOI: 10.1016/j.biopha.2021.112477] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/14/2021] [Accepted: 11/23/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is the world's second-leading cause of cancer-related mortality, continuing to make it a serious healthcare concern. Even though the prevalence of GC reduces, the prognosis for GC patients remains poor in terms of a lack of reliable biomarkers to diagnose early GC and predict chemosensitivity and recurrence. METHODS AND MATERIAL We integrated the gene expression patterns of gastric cancers from four RNAseq datasets (GSE113255, GSE142000, GSE118897, and GSE130823) from Gene Expression Omnibus (GEO) database to recognize differentially expressed genes (DEGs) between normal and GC samples. A gene co-expression network was built using weighted co-expression network analysis (WGCNA). Furthermore, RT-qPCR was performed to validate the in silico results. RESULTS The red modules in GSE113255, Turquoise in GSE142000, Brown in GSE118897, and the green-yellow module in GSE130823 datasets were found to be highly correlated with the anatomical site of GC. ITGAX, CCL14, ADHFE1, and HOXB13) as the hub gene are differentially expressed in tumor and non-tumor gastric tissues in this study. RT-qPCR demonstrated a high level of the expression of this gene. CONCLUSION The expression levels of ITGAX, CCL14, ADHFE1, and HOXB13 in GC tumor tissues are considerably greater than in adjacent normal tissues. Systems biology approaches identified that these genes could be possible GC marker genes, providing ideas for other experimental studies in the future.
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Sui T, Qiu B, Qu J, Wang Y, Ran K, Han W, Peng X. Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner. PHARMACEUTICAL BIOLOGY 2021; 59:1566-1575. [PMID: 34767490 PMCID: PMC8592593 DOI: 10.1080/13880209.2021.1998140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/09/2021] [Accepted: 10/21/2021] [Indexed: 06/13/2023]
Abstract
CONTEXT Gambogic amide (GA-amide) is a non-peptide molecule that has high affinity for tropomyosin receptor kinase A (TrkA) and possesses robust neurotrophic activity, but its effect on angiogenesis is unclear. OBJECTIVE The study investigates the antiangiogenic effect of GA-amide on endothelial cells (ECs). MATERIALS AND METHODS The viability of endothelial cells (ECs) treated with 0.1, 0.15, 0.2, 0.3, 0.4, and 0.5 μM GA-amide for 48 h was detected by MTS assay. Wound healing and angiogenesis assays were performed on cells treated with 0.2 μM GA-amide. Chicken eggs at day 7 post-fertilization were divided into the dimethyl sulfoxide (DMSO), bevacizumab (40 μg), and GA-amide (18.8 and 62.8 ng) groups to assess the antiangiogenic effect for 3 days. mRNA and protein expression in cells treated with 0.1, 0.2, 0.4, 0.8, and 1.2 μM GA-amide for 6 h was detected by qRT-PCR and Western blots, respectively. RESULTS GA-amide inhibited HUVEC (IC50 = 0.1269 μM) and NhEC (IC50 = 0.1740 μM) proliferation, induced cell apoptosis, and inhibited the migration and angiogenesis at a relatively safe dose (0.2 μM) in vitro. GA-amide reduced the number of capillaries from 56 ± 14.67 (DMSO) to 20.3 ± 5.12 (62.8 ng) in chick chorioallantoic membrane (CAM) assay. However, inactivation of TrkA couldn't reverse the antiangiogenic effect of GA-amide. Moreover, GA-amide suppressed the expression of VEGF and VEGFR2, and decreased activation of the AKT/mTOR and PLCγ/Erk1/2 pathways. CONCLUSIONS Considering the antiangiogenic effect of GA-amide, it might be developed as a useful agent for use in clinical combination therapies.
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Affiliation(s)
- Tongtong Sui
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Bojun Qiu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Jiaorong Qu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yuxin Wang
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Kunnian Ran
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Wei Han
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, China
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Tikhonov D, Kulikova L, Rudnev V, Kopylov AT, Taldaev A, Stepanov A, Malsagova K, Izotov A, Enikeev D, Potoldykova N, Kaysheva A. Changes in Protein Structural Motifs upon Post-Translational Modification in Kidney Cancer. Diagnostics (Basel) 2021; 11:diagnostics11101836. [PMID: 34679534 PMCID: PMC8534394 DOI: 10.3390/diagnostics11101836] [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: 08/18/2021] [Revised: 09/20/2021] [Accepted: 10/01/2021] [Indexed: 11/28/2022] Open
Abstract
Post-translational modification (PTM) leads to conformational changes in protein structure, modulates the biological function of proteins, and, consequently, changes the signature of metabolic transformations and the immune response in the body. Common PTMs are reversible and serve as a mechanism for modulating metabolic trans-formations in cells. It is likely that dysregulation of post-translational cellular signaling leads to abnormal proliferation and oncogenesis. We examined protein PTMs in the blood samples from patients with kidney cancer. Conformational changes in proteins after modification were analyzed. The proteins were analyzed using ultra-high resolution HPLC-MS/MS and structural analysis was performed with the AMBER and GROMACS software packages. Fifteen proteins containing PTMs were identified in blood samples from patients with kidney cancer. For proteins with PDB structures, a comparative analysis of the structural changes accompanying the modifications was performed. Results revealed that PTMs are localized in stable and compact space protein globule motifs that are exposed to a solvent. The phenomenon of modification is accompanied, as a rule, by an increase in the area available for the solvent of the modified amino acid residue and its active environment.
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Affiliation(s)
- Dmitry Tikhonov
- Institute of Mathematical Problems of Biology RAS—The Branch of Keldysh Institute of Applied Mathematics of Russian Academy of Sciences, 142290 Pushchino, Russia; (D.T.); (L.K.)
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Liudmila Kulikova
- Institute of Mathematical Problems of Biology RAS—The Branch of Keldysh Institute of Applied Mathematics of Russian Academy of Sciences, 142290 Pushchino, Russia; (D.T.); (L.K.)
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Vladimir Rudnev
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia;
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
| | - Arthur T. Kopylov
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
| | - Amir Taldaev
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
- Institute of Urology and Reproductive Health, Sechenov University, 119121 Moscow, Russia; (D.E.); (N.P.)
| | - Alexander Stepanov
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
| | - Kristina Malsagova
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
- Correspondence: ; Tel.: +7-499-764-9878
| | - Alexander Izotov
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
| | - Dmitry Enikeev
- Institute of Urology and Reproductive Health, Sechenov University, 119121 Moscow, Russia; (D.E.); (N.P.)
| | - Natalia Potoldykova
- Institute of Urology and Reproductive Health, Sechenov University, 119121 Moscow, Russia; (D.E.); (N.P.)
| | - Anna Kaysheva
- V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.T.K.); (A.T.); (A.S.); (A.I.); (A.K.)
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Zhang L, Jiao C, Liu L, Wang A, Tang L, Ren Y, Huang P, Xu J, Mao D, Liu L. NLRC5: A Potential Target for Central Nervous System Disorders. Front Immunol 2021; 12:704989. [PMID: 34220868 PMCID: PMC8250149 DOI: 10.3389/fimmu.2021.704989] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/07/2021] [Indexed: 12/22/2022] Open
Abstract
Nucleotide oligomerization domain-like receptors (NLRs), a class of pattern recognition receptors, participate in the host’s first line of defense against invading pathogenic microorganisms. NLR family caspase recruitment domain containing 5 (NLRC5) is the largest member of the NLR family and has been shown to play an important role in inflammatory processes, angiogenesis, immunity, and apoptosis by regulating the nuclear factor-κB, type I interferon, and inflammasome signaling pathways, as well as the expression of major histocompatibility complex I genes. Recent studies have found that NLRC5 is also associated with neuronal development and central nervous system (CNS) diseases, such as CNS infection, cerebral ischemia/reperfusion injury, glioma, multiple sclerosis, and epilepsy. This review summarizes the research progress in the structure, expression, and biological characteristics of NLRC5 and its relationship with the CNS.
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Affiliation(s)
- Lu Zhang
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Cui Jiao
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lingjuan Liu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Aiping Wang
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li Tang
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Ren
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peng Huang
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jie Xu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Dingan Mao
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Liqun Liu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Children's Brain Development and Brain Injury Research Office, The Second Xiangya Hospital, Central South University, Changsha, China
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Zhang J, Zheng Y, Zhao Y, Zhang Y, Liu Y, Ma F, Wang X, Fu J. Andrographolide ameliorates neuroinflammation in APP/PS1 transgenic mice. Int Immunopharmacol 2021; 96:107808. [PMID: 34162168 DOI: 10.1016/j.intimp.2021.107808] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/29/2021] [Accepted: 05/21/2021] [Indexed: 11/18/2022]
Abstract
Alzheimer's disease is a devastating neurodegenerative disorder, with no disease-modifying treatment available yet. There is increasing evidence that neuroinflammation plays a critical role in the pathogenesis of AD. Andrographolide (Andro), a labdane diterpene extracted from the herb Andrographis paniculata, has been reported to exhibit neuroprotective property in central nervous system diseases. However, its effects on Aβ and Aβ-induced neuroinflammation have not yet been studied. In the present study, we found that Andro administration significantly alleviated cognitive impairments, reduced amyloid-β deposition, inhibited microglial activation, and decreased the secretion of proinflammatory factors in APP/PS1 mice. Furthermore, transcriptome sequencing analysis revealed that Andro could significantly decrease the expression of Itgax, TLR2, CD14, CCL3, CCL4, TLR1, and C3ar1 in APP/PS1 mice, which was further validated by qRT-PCR. Our results suggest that Andro might be a potential therapeutic drug for AD by regulating neuroinflammation.
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Affiliation(s)
- Jiawei Zhang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yaling Zheng
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yao Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yaxuan Zhang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yu Liu
- Department of Medicine, Shanghai Eighth People's Hospital, Shanghai 200235, China
| | - Fang Ma
- Department of Neurosurgery, Lushi People's Hospital, Henan 472200, China
| | - Xiuzhe Wang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
| | - Jianliang Fu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
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Cruz-Acuña R, Vunjak-Novakovic G, Burdick JA, Rustgi AK. Emerging technologies provide insights on cancer extracellular matrix biology and therapeutics. iScience 2021; 24:102475. [PMID: 34027324 PMCID: PMC8131321 DOI: 10.1016/j.isci.2021.102475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Recent engineering technologies have transformed traditional perspectives of cancer to include the important role of the extracellular matrix (ECM) in recapitulating the malignant behaviors of cancer cells. Novel biomaterials and imaging technologies have advanced our understanding of the role of ECM density, structure, mechanics, and remodeling in tumor cell-ECM interactions in cancer biology and have provided new approaches in the development of cancer therapeutics. Here, we review emerging technologies in cancer ECM biology and recent advances in engineered systems for evaluating cancer therapeutics and provide new perspectives on how engineering tools present an opportunity for advancing the modeling and treatment of cancer. This review offers the cell biology and cancer cell biology communities insight into how engineering tools can improve our understanding of cancer ECM biology and therapeutic development.
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Affiliation(s)
- Ricardo Cruz-Acuña
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Jason A. Burdick
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Sui Y, Lu K, Fu L. Prediction and analysis of novel key genes ITGAX, LAPTM5, SERPINE1 in clear cell renal cell carcinoma through bioinformatics analysis. PeerJ 2021; 9:e11272. [PMID: 33976979 PMCID: PMC8063882 DOI: 10.7717/peerj.11272] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Background Clear Cell Renal Cell Carcinoma (CCRCC) is the most aggressive subtype of Renal Cell Carcinoma (RCC) with high metastasis and recurrence rates. This study aims to find new potential key genes of CCRCC. Methods Four gene expression profiles (GSE12606, GSE53000, GSE68417, and GSE66272) were downloaded from the Gene Expression Omnibus (GEO) database. The TCGA KIRC data was downloaded from The Cancer Genome Atlas (TCGA). Using GEO2R, the differentially expressed genes (DEG) in CCRCC tissues and normal samples were analyzed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed in DAVID database. A protein-protein interaction (PPI) network was constructed and the hub gene was predicted by STRING and Cytoscape. GEPIA and Kaplan-Meier plotter databases were used for further screening of Key genes. Expression verification and survival analysis of key genes were performed using TCGA database, GEPIA database, and Kaplan-Meier plotter. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of key genes in CCRCC, which is plotted by R software based on TCGA database. UALCAN database was used to analyze the relationship between key genes and clinical pathology in CCRCC and the methylation level of the promoter of key genes in CCRCC. Results A total of 289 up-regulated and 449 down-regulated genes were identified based on GSE12606, GSE53000, GSE68417, and GSE66272 profiles in CCRCC. The upregulated DEGs were mainly enriched with protein binding and PI3K-Akt signaling pathway, whereas down-regulated genes were enriched with the integral component of the membrane and metabolic pathways. Next, the top 35 genes were screened out from the PPI network according to Degree, and three new key genes ITGAX, LAPTM5 and SERPINE1 were further screened out through survival and prognosis analysis. Further results showed that the ITGAX, LAPTM5, and SERPINE1 levels in CCRCC tumor tissues were significantly higher than those in normal tissues and were associated with poor prognosis. ROC curve shows that ITGAX, LAPTM5, and SERPINE1 have good diagnostic value with good specificity and sensitivity. The promoter methylation levels of ITGAX, LAPTM5 and SERPINE1 in CCRCC tumor tissues were significantly lower than those in normal tissues. We also found that key genes were associated with clinical pathology in CCRCC. Conclusion ITGAX, LAPTM5, and SERPINE1 were identified as novel key candidate genes that could be used as prognostic biomarkers and potential therapeutic targets for CCRCC.
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Affiliation(s)
- Yingli Sui
- Institute of Chronic Disease, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Kun Lu
- Institute of Chronic Disease, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Lin Fu
- Institute of Chronic Disease, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
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Wang X, Chen S, Xiang H, Liang Z, Lu H. Role of sphingosine-1-phosphate receptors in vascular injury of inflammatory bowel disease. J Cell Mol Med 2021; 25:2740-2749. [PMID: 33595873 PMCID: PMC7957208 DOI: 10.1111/jcmm.16333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/14/2022] Open
Abstract
Sphingosine‐1‐phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR‐targeted therapies.
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Affiliation(s)
- Xuewen Wang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Liang
- Department of Clinical laboratory, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, China
| | - Hongwei Lu
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
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Zhao J, Zhang X, Du Y, Zhou L, Dong Z, Zhao J, Lu J. Allogenic mouse cell vaccine inhibits lung cancer progression by inhibiting angiogenesis. Hum Vaccin Immunother 2021; 17:35-50. [PMID: 32460680 DOI: 10.1080/21645515.2020.1759996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: This research investigated the therapeutic effect of an allogeneic mouse brain microvascular endothelial cell vaccine on lung cancer and further elucidated its potential anti-angiogenic mechanism. Materials & methods: The immune effect of the allogeneic bEnd.3 vaccine and DC vaccine loaded with bEnd.3 antigen on the subcutaneous transplantation of Lewis lung cancer (LLC) was assessed by ELISA, the CCK test and the CTL killing test. The mechanism was preliminarily revealed by immunohistochemistry and immunoblot analysis. Results: This study revealed that tumor volume was decreased (p < .01) and the survival was prolonged significantly (p < .05) by the bEnd.3 vaccine in subcutaneous LLC transplantation in the vaccine prevention group. In contrast, both tumor volume in the serum therapeutic group and survival of bEnd.3 vaccine were not significantly different from those of the control group (p > .05). Importantly, tumor volume and survival of the T lymphocyte therapeutic group were decreased and prolonged (p < .05). In addition, both tumor volume and survival of DC vaccine loaded with bEnd.3 in the vaccine prevention group were decreased and prolonged significantly (p < .01). Furthermore, bEnd.3 vaccine and DC vaccine loaded with bEnd.3 both produced the activity of killing bEnd.3 target cells in vitro.The reason may induce the immune mice to produce anti-VEGFR-II, anti-endoglin and anti-integrin αν antibodies to have an anti-angiogenesis function. Conclusion: The allogeneic mouse bEnd.3 cell vaccine can block angiogenesis and prevent the development of lung cancer transplantation tumors.
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Affiliation(s)
- Jun Zhao
- Department of Oncology, Changzhi People's Hospital , Changzhi, China.,Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University , Zhengzhou, China
| | - Xiaoling Zhang
- Department of Oncology, Changzhi People's Hospital , Changzhi, China
| | - Yunyi Du
- Department of Oncology, Changzhi People's Hospital , Changzhi, China
| | - Lurong Zhou
- Quality Control Department, Changzhi People's Hospital , Changzhi, China
| | - Ziming Dong
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University , Zhengzhou, China.,Collaborative Innovation Center of Henan Province for Cancer Chemoprevention , Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University , Zhengzhou, China
| | - Jimin Zhao
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University , Zhengzhou, China.,Collaborative Innovation Center of Henan Province for Cancer Chemoprevention , Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University , Zhengzhou, China
| | - Jing Lu
- Department of Pathophysiology, College of Basic Medical Sciences, Zhengzhou University , Zhengzhou, China.,Collaborative Innovation Center of Henan Province for Cancer Chemoprevention , Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University , Zhengzhou, China
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35
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Han Y, Wang J, Xu B. Novel biomarkers and prediction model for the pathological complete response to neoadjuvant treatment of triple-negative breast cancer. J Cancer 2021; 12:936-945. [PMID: 33403050 PMCID: PMC7778555 DOI: 10.7150/jca.52439] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 11/12/2020] [Indexed: 12/16/2022] Open
Abstract
Objective: To develop and validate a prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NCT) of triple-negative breast cancer (TNBC). Methods: We systematically searched Gene Expression Omnibus, ArrayExpress, and PubMed for the gene expression profiles of operable TNBC accessible to NCT. Molecular heterogeneity was detected with hierarchical clustering method, and the biological profiles of differentially expressed genes were investigated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses, and Gene Set Enrichment Analysis (GSEA). Next, machine-learning algorithms including random-forest analysis and least absolute shrinkage and selection operator (LASSO) analysis were synchronously performed and, then, the intersected proportion of significant genes was undergone binary logistic regression to fulfill variables selection. The predictive response score (pRS) system was built as the product of the gene expression and coefficient obtained from the logistic analysis. Last, the cohorts were randomly divided in a 7:3 ratio into training cohort and validation cohort for the introduction of a robust model, and a nomogram was constructed with the independent predictors for pCR rate. Results: A total of 217 individuals from four cohort datasets (GSE32646, GSE25065, GSE25055, GSE21974) with complete clinicopathological information were included. Based on the microarray data, a six-gene panel (ATP4B, FBXO22, FCN2, RRP8, SMERK2, TET3) was identified. A robust nomogram, adopting pRS and clinical tumor size stage, was established and the performance was successively validated by calibration curves and receiver operating characteristic curves with the area under curve 0.704 and 0.756, respectively. Results of GSEA revealed that the biological processes including apoptosis, hypoxia, mTORC1 signaling and myogenesis, and oncogenic features of EGFR and RAF were in proactivity to attribute to an inferior response. Conclusions: This study provided a robust prediction model for pCR rate and revealed potential mechanisms of distinct response to NCT in TNBC, which were promising and warranted to further validate in the perspective.
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Affiliation(s)
- Yiqun Han
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Jiayu Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
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36
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Expression and Prognostic Analysis of Integrins in Gastric Cancer. JOURNAL OF ONCOLOGY 2020; 2020:8862228. [PMID: 33335550 PMCID: PMC7722456 DOI: 10.1155/2020/8862228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 12/14/2022]
Abstract
Background Integrins are involved in the biological process of a variety of cancers, but their importance in the diagnosis and prognosis of gastric cancer (GC) is still unclear. Therefore, this study aimed at exploring the significance of ITG gene expression in GC to evaluate its diagnosis and prognosis. Methods GEPIA data were used to evaluate the mRNA expression of ITG genes in GC patients. The prognostic value of these genes was assessed by analyzing their mRNA expression using the Kaplan–Meier curve. The biological function of ITG genes was evaluated by GC tissue sequencing combined with GSEA bioinformatics. Based on the sequencing data, ITGA5 with the largest expression difference was selected for verification, and RT-PCR was used to verify its mRNA expression level in 40 pairs of GC and normal tissues. Results ITG (A2, A3, A4, A5, A6, A11, AE, AL, AM, AV, AX, B1, B2, B4, B5, B6, and B8) was highly expressed in GC tissues, while ITGA8 was low, compared with their expression in normal tissues. RNA-seq data shows that ITG (A2, A5, A11, AV, and B1) expression was associated with poor prognosis and overall survival. In addition, combined with the results of GC tissue mRNA sequencing, it was further found that the differentially expressed genes in the ITGs genes. ITGA5 was highly expressed in GC tissues compared with its expression in normal tissues, as evaluated by qRT–PCR (P < 0.001) and ROC (P < 0.001, AUC (95% CI) = 0.747 (0.641–0.851)), and confirmed that ITGA5 expression was a potential diagnostic marker for GC. Bioinformatics analysis revealed that the signaling pathway involved in ITGA5 was mainly enriched in focal adhesion, ECM-receptor interaction, and PI3K-AKT and was mainly involved in biological processes such as cell adhesion, extracellular matrix, and cell migration. Conclusion This study suggested that ITGs were associated with the diagnosis and prognosis of GC and discovered the prognostic value and biological role of ITGA5 in GC. Thus, ITGA5 might be used as a potential diagnostic marker for GC.
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37
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Jeong JH, Ojha U, Lee YM. Pathological angiogenesis and inflammation in tissues. Arch Pharm Res 2020; 44:1-15. [PMID: 33230600 PMCID: PMC7682773 DOI: 10.1007/s12272-020-01287-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022]
Abstract
The role of angiogenesis in the growth of organs and tumors is widely recognized. Vascular-organ interaction is a key mechanism and a concept that enables an understanding of all biological phenomena and normal physiology that is essential for human survival under pathological conditions. Recently, vascular endothelial cells have been classified as a type of innate immune cells that are dependent on the pathological situations. Moreover, inflammatory cytokines and signaling regulators activated upon exposure to infection or various stresses play crucial roles in the pathological function of parenchymal cells, peripheral immune cells, stromal cells, and cancer cells in tissues. Therefore, vascular-organ interactions as a vascular microenvironment or tissue microenvironment under physiological and pathological conditions are gaining popularity as an interesting research topic. Here, we review vascular contribution as a major factor in microenvironment homeostasis in the pathogenesis of normal as well as cancerous tissues. Furthermore, we suggest that the normalization strategy of pathological angiogenesis could be a promising therapeutic target for various diseases, including cancer.
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Affiliation(s)
- Ji-Hak Jeong
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea.,College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Uttam Ojha
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea
| | - You Mie Lee
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea. .,College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
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38
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Lu T, Yang X, Shi Y, Zhao M, Bi G, Liang J, Chen Z, Huang Y, Jiang W, Lin Z, Xi J, Wang S, Yang Y, Zhan C, Wang Q, Tan L. Single-cell transcriptome atlas of lung adenocarcinoma featured with ground glass nodules. Cell Discov 2020; 6:69. [PMID: 33083004 PMCID: PMC7536439 DOI: 10.1038/s41421-020-00200-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 07/30/2020] [Indexed: 12/13/2022] Open
Abstract
As an early type of lung adenocarcinoma, ground glass nodule (GGN) has been detected increasingly and now accounts for most lung cancer outpatients. GGN has a satisfactory prognosis and its characteristics are quite different from solid adenocarcinoma (SADC). We compared the GGN adenocarcinoma (GGN-ADC) with SADC using the single-cell RNA sequencing (scRNA-seq) to fully understand GGNs. The tumor samples of five patients with lung GGN-ADCs and five with SADCs underwent surgery were digested to a single-cell suspension and analyzed using 10× Genomic scRNA-seq techniques. We obtained 60,459 cells and then classified them as eight cell types, including cancer cells, endothelial cells, fibroblasts, T cells, B cells, Nature killer cells, mast cells, and myeloid cells. We provided a comprehensive description of the cancer cells and stromal cells. We found that the signaling pathways related to cell proliferation were downregulated in GGN-ADC cancer cells, and stromal cells had different effects in GGN-ADC and SADC based on the analyses of scRNA-seq results. In GGN-ADC, the signaling pathways of angiogenesis were downregulated, fibroblasts expressed low levels of some collagens, and immune cells were more activated. Furthermore, we used flow cytometry to isolate the cancer cells and T cells in 12 GGN-ADC samples and in an equal number of SADC samples, including CD4+ T and CD8+ T cells, and validated the expression of key molecules by quantitative real-time polymerase chain reaction analyses. Through comprehensive analyses of cell phenotypes in GGNs, we provide deep insights into lung carcinogenesis that will be beneficial in lung cancer prevention and therapy.
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Affiliation(s)
- Tao Lu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Xiaodong Yang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Yu Shi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Mengnan Zhao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Wei Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Zongwu Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Junjie Xi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Shuai Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Yong Yang
- Department of Cardio-Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006 China
- Department of Thoracic Surgery, Suzhou Hospital affiliated to Nanjing Medical University, Suzhou, Jiangsu 215001 China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
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Su CY, Li JQ, Zhang LL, Wang H, Wang FH, Tao YW, Wang YQ, Guo QR, Li JJ, Liu Y, Yan YY, Zhang JY. The Biological Functions and Clinical Applications of Integrins in Cancers. Front Pharmacol 2020; 11:579068. [PMID: 33041823 PMCID: PMC7522798 DOI: 10.3389/fphar.2020.579068] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/24/2020] [Indexed: 12/12/2022] Open
Abstract
Integrins are the adhesion molecules and receptors of extracellular matrix (ECM). They mediate the interactions between cells-cells and cells-ECM. The crosstalk between cancer cells and their microenvironment triggers a variety of critical signaling cues and promotes the malignant phenotype of cancer. As a type of transmembrane protein, integrin-mediated cell adhesion is essential in regulating various biological functions of cancer cells. Recent evidence has shown that integrins present on tumor cells or tumor-associated stromal cells are involved in ECM remodeling, and as mechanotransducers sensing changes in the biophysical properties of the ECM, which contribute to cancer metastasis, stemness and drug resistance. In this review, we outline the mechanism of integrin-mediated effects on biological changes of cancers and highlight the current status of clinical treatments by targeting integrins.
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Affiliation(s)
- Chao-Yue Su
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jing-Quan Li
- The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Ling-Ling Zhang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Hui Wang
- Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Feng-Hua Wang
- Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yi-Wen Tao
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yu-Qing Wang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qiao-Ru Guo
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jia-Jun Li
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yun Liu
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yan-Yan Yan
- Institute of Immunology and School of Medicine, Shanxi Datong University, Datong, China
| | - Jian-Ye Zhang
- The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.,The First Affiliated Hospital, Hainan Medical University, Haikou, China
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Cheng C, Shou Q, Lang J, Jin L, Liu X, Tang D, Yang Z, Fu H. Gehua Jiecheng Decoction Inhibits Diethylnitrosamine-Induced Hepatocellular Carcinoma in Mice by Improving Tumor Immunosuppression Microenvironment. Front Pharmacol 2020; 11:809. [PMID: 32547401 PMCID: PMC7272686 DOI: 10.3389/fphar.2020.00809] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 05/18/2020] [Indexed: 12/11/2022] Open
Abstract
Gehua Jiecheng Decoction (GHJCD), a famous traditional Chinese medicine, has been used in the prevention and treatment of precancerous lesion of liver cancer, but its active mechanism has not been reported. This study aimed to evaluate the therapeutic effect of GHJCD on diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in mice and the mechanism of this effect. We found that GHJCD effectively inhibited the occurrence of liver cancer and reduced the tumor area. The ratio of regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) in HCC microenvironment was down-regulated, whereas that of CD8 T and effective CD8 T cells was up-regulated. In addition, the expression levels of inflammatory factors IL-6, IL-10, TNF-α, and CCL-2 in the liver were inhibited, whereas those of the angiogenesis related molecules CD31 and VEGF were decreased. Moreover, WNT1, β-catenin, NF-kB, p-MAPK, p-AKT, and p-SRC content in the liver decreased, whereas APC content increased. These results suggested that GHJCD exerted a good inhibitory effect on liver cancer induced by DEN and thus may have a multi-target effect; GHJCD not only antagonized the immunosuppressive effect of the microenvironment of liver cancer but also exerted strong anti-inflammatory and antiangiogenesis effects.
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Affiliation(s)
- Changpei Cheng
- Affiliated First Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China.,Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China.,Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qiyang Shou
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiali Lang
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Jin
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xia Liu
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dongxin Tang
- Affiliated First Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zhu Yang
- Affiliated First Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Huiying Fu
- Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, China
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Zou Y, Wu F, Liu Q, Deng X, Hai R, He X, Zhou X. Downregulation of miRNA‑328 promotes the angiogenesis of HUVECs by regulating the PIM1 and AKT/mTOR signaling pathway under high glucose and low serum condition. Mol Med Rep 2020; 22:895-905. [PMID: 32626978 PMCID: PMC7339821 DOI: 10.3892/mmr.2020.11141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 04/08/2020] [Indexed: 01/02/2023] Open
Abstract
Vascular complications are the primary reason for disability and mortality associated with diabetes mellitus (DM), and numerous microRNAs (miRNAs/miRs) are involved in the process, such as miR‑122, miR‑24 and miR‑423. It has been reported that miR‑328 regulates DM and cardiovascular disease; however, the role and mechanism of action underlying miR‑328 in HUVECs is not completely understood. The present study aimed to investigate the role and mechanism of action underlying the effects of miR‑328 on the functions of HUVECs. To simulate hyperglycemia combined with ischemia‑induced tissue starvation, HUVECs were cultured in endothelial cell medium with 25 mmol/l D‑glucose and 2% FBS for 24 h [high glucose (HG) + 2% FBS group]. HUVEC miR‑328 expression levels were detected by reverse transcription‑quantitative PCR. Cell migration, cytotoxicity and tube‑like structure formation were analyzed using wound healing, Cell Counting Kit‑8 and tube formation assays, respectively. Following transfection with miR‑328 inhibitor, miR‑328 expression was downregulated in HUVECs. Protein expression levels were determined by western blotting. Compared with the control group, the migration and tube‑like structure formation of HUVECs were decreased, and cell cytotoxicity was increased in the HG + 2% FBS group. The protein expression levels of vascular endothelial growth factor were also decreased, and the expression levels of miRNA‑328 in the HG + 2% FBS group were increased compared with the control group. However, miRNA‑328 downregulation reversed the aforementioned effects. Further experiments indicated that the AKT signaling pathway was inhibited in the HG + 2% FBS group; however, miR‑328 downregulation activated the AKT/mTOR signaling pathway, which was blocked by the AKT signaling pathway inhibitor, perifosine. Gene prediction and western blotting demonstrated that miR‑328 displayed a regulatory role via Pim‑1 proto‑oncogene, serine/threonine kinase (PIM1). In conclusion, miR‑328 expression was upregulated and angiogenesis was inhibited when HUVECs were subjected to high glucose and low serum conditions. miR‑328 downregulation enhanced angiogenesis by increasing PIM1 expression and activating the AKT/mTOR signaling pathway in HUVECs under high glucose and low serum conditions.
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Affiliation(s)
- Yan Zou
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Fei Wu
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Qi Liu
- Department of Pediatrics, Nanchong Central Hospital, Nanchong, Sichuan 637000, P.R. China
| | - Xian Deng
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Rui Hai
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Xuemei He
- Medical Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Xiangyu Zhou
- Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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42
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Wu Q, Zhong H, Jiao L, Wen Y, Zhou Y, Zhou J, Lu X, Song X, Ying B. MiR-124-3p inhibits the migration and invasion of Gastric cancer by targeting ITGB3. Pathol Res Pract 2019; 216:152762. [PMID: 31836324 DOI: 10.1016/j.prp.2019.152762] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/11/2019] [Accepted: 11/25/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gastric cancer is one of the major malignant tumors in the world. Integrins expressed in cancer cells can promote tumor progression and migration. MiRNAs can inhibit the expression of target genes by directly binding to their mRNAs and can affect various important biological processes. The aim of this study was to investigate the role of miR-124- 3p and ITGB3 in gastric cancer. METHODS RT-PCR and western blot are used to detect the expression of miR-124-3p, ITGB3 and integrin β3 in gastric cancer tissues and cells. The wound healing, CCK-8 assay, transwell migration and invasion assay were performed to determine the cell proliferation, migration and invasion. What's more, bioinformatics prediction and luciferase assay was conducted to demonstrated the binding efficiency between miR-124-3p and ITGB3. RESULTS We verified that ITGB3 and miR-124-3p changes the migration and invasion of gastric cancer cells in vitro. The overexpression or silencing of miR-124-3p inhibited or promoted the proliferation, migration and invasion of both selected gastric cancer cells, and ITGB3 is just the reverse. Meanwhile, we validated that ITGB3 is the target of miR-124-3p by bioinformatics prediction and luciferase assay. Lastly, the expression of ITGB3 in 40 pairs of gastric cancer tissues were significantly higher than that in the adjacent normal tissues, while the expression level of miR-124-3p was significantly decreased in cancer tissues. CONCLUSIONS miR-124-3p inhibits the migration and invasion of Gastric cancer by targeting ITGB3 in gastric cancer cells. Our results suggested that miR-124-3p and ITGB3 may reasonably serve as a promising therapeutic target.
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Affiliation(s)
- Qian Wu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Huiyu Zhong
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lin Jiao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yang Wen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yi Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaojun Lu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xingbo Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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43
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Danilucci TM, Santos PK, Pachane BC, Pisani GFD, Lino RLB, Casali BC, Altei WF, Selistre-de-Araujo HS. Recombinant RGD-disintegrin DisBa-01 blocks integrin α vβ 3 and impairs VEGF signaling in endothelial cells. Cell Commun Signal 2019; 17:27. [PMID: 30894182 PMCID: PMC6425665 DOI: 10.1186/s12964-019-0339-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 03/12/2019] [Indexed: 12/18/2022] Open
Abstract
Background Integrins mediate cell adhesion, migration, and survival by connecting the intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the interaction between αvβ3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. DisBa-01, a recombinant His-tag fusion, RGD-disintegrin from Bothrops alternatus snake venom, binds to αvβ3 integrin with nanomolar affinity blocking cell adhesion to the extracellular matrix. Here we present in vitro evidence of a direct interference of DisBa-01 with αvβ3/VEGFR2 cross-talk and its downstream pathways. Methods Human umbilical vein (HUVECs) were cultured in plates coated with fibronectin (FN) or vitronectin (VN) and tested for migration, invasion and proliferation assays in the presence of VEGF, DisBa-01 (1000 nM) or VEGF and DisBa-01 simultaneously. Phosphorylation of αvβ3/VEGFR2 receptors and the activation of intracellular signaling pathways were analyzed by western blotting. Morphological alterations were observed and quantified by fluorescence confocal microscopy. Results DisBa-01 treatment of endothelial cells inhibited critical steps of VEGF-mediated angiogenesis such as migration, invasion and tubulogenesis. The blockage of αvβ3/VEGFR2 cross-talk by this disintegrin decreases protein expression and phosphorylation of VEGFR2 and β3 integrin subunit, regulates FAK/SrC/Paxillin downstream signals, and inhibits ERK1/2 and PI3K pathways. These events result in actin re-organization and inhibition of HUVEC migration and adhesion. Labelled-DisBa-01 colocalizes with αvβ3 integrin and VEGFR2 in treated cells. Conclusions Disintegrin inhibition of αvβ3 integrin blocks VEGFR2 signalling, even in the presence of VEGF, which impairs the angiogenic mechanism. These results improve our understanding concerning the mechanisms of pharmacological inhibition of angiogenesis. Electronic supplementary material The online version of this article (10.1186/s12964-019-0339-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Taís M Danilucci
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Patty K Santos
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Bianca C Pachane
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Graziéle F D Pisani
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Rafael L B Lino
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Bruna C Casali
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Wanessa F Altei
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Heloisa S Selistre-de-Araujo
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, Rod. Washington Luis, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil.
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