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Xiao M, Su S, He X, Song L, Wang D. DPH2 is a biomarker associated with cell death, immunity and prognosis based on pan-cancer analysis. Discov Oncol 2025; 16:149. [PMID: 39928200 PMCID: PMC11811350 DOI: 10.1007/s12672-025-01924-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/04/2025] [Indexed: 02/11/2025] Open
Abstract
OBJECTIVE DPH2, also known as DPH2L2, is one of two human genes similar to yeast dph2. One DPH2 variant has been linked to diphthamide syndrome, a disorder affecting ribosome function. While studies on DPH2 in a single cancer type have been documented, no comprehensive investigations of DPH2 across pan-cancer have been reported, its role in tumor pathogenesis and development remains unclear. METHODS The predictive significance and immune and biological roles of DPH2 in 33 different cancer types were investigated. We conducted a comprehensive analysis of DPH2 in pan-cancer using various bioinformatics tools, including expression, prognosis, its association with immune infiltration, cell death, methylation, and many other aspects. In addition, qRT-PCR and immunohistochemistry experiments confirmed DPH2 expression in prostate adenocarcinoma (PRAD) tissues, DPH2 biological function in PRAD was assessed using in vitro experiments, and used immunofluorescence to validate the proteins associated with DPH2. RESULTS The DPH2 expression was high in most tumors and showed significant correlations with OS and PFI. Our experimental findings confirmed that DPH2 is highly expressed in PRAD, while DPH2 knockdown inhibited prostate cancer cell proliferation, invasion, and migration. Furthermore, our data suggest that DPH2 may significantly influence immune cell infiltration. DPH2 was significantly correlated with cell death-related genes. DPH2 can influence cancer progression through changes in DNA methylation levels, or N6-methyladenosine site modification. GSEA and GSVA revealed that DPH2 levels were significantly associated with enrichment for oncogenic and immune-related pathways. Drug sensitivity analysis revealed that the elevated DPH2 expression is linked to development of resistance against numerous anticancer medications. CONCLUSION DPH2 has potential as a novel prognostic biomarker that may significantly impact tumor onset and progression. Consequently, DPH2 could serve as a target for new cancer treatments.
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Affiliation(s)
- Maolin Xiao
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
- Chongqing Medical University, Chongqing, China
| | - Shuai Su
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
- Chongqing Medical University, Chongqing, China
| | - Xiangbiao He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
- Chongqing Medical University, Chongqing, China
| | - Liangdong Song
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
- Chongqing Medical University, Chongqing, China
| | - Delin Wang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China.
- Chongqing Medical University, Chongqing, China.
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Ji Y, Li L, Li W, Li L, Ma Y, Li Q, Chen X, Zhao W, Zhu H, Huo J, Wu M. Xiaoai Jiedu recipe reduces cell survival and induces apoptosis in hepatocellular carcinoma by stimulating autophagy via the AKT/mTOR pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 339:119135. [PMID: 39586558 DOI: 10.1016/j.jep.2024.119135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Xiaoai Jiedu recipe (XJR) is a traditional Chinese medicine formulation used in clinical settings to treat liver cancer. It has shown promising effectiveness by combining herbal and animal-derived ingredients, offering a new approach to cancer treatment. However, its mechanism of action is poorly understood. AIM OF THE STUDY The molecular processes underlying the inhibitory effects of the XJR on hepatocellular cancer (HCC) were investigated. MATERIALS AND METHODS The primary chemical components of XJR and associated disease targets relevant to HCC were anticipated and compiled using a database. The potential targets and processes by which XJR influenced HCC were investigated using GO and KEGG enrichment analyses, as well as protein-protein interaction (PPI) networks. Transmission electron microscopy, laser confocal microscopy, and Western blotting were used to evaluate autophagy, while CCK-8 assays measured cell viability and Western blotting and flow cytometry evaluated apoptosis. In vivo assays were conducted employing an HCC xenograft mouse model. RESULTS Network pharmacology analysis identified 456 intersecting targets between XJR and HCC. The top five active components are quercetin, cholesterol, jaceosidine, eupafolin, and oleanolic acid. The key targets include TP53, AKT1, IL6, EGFR, SRC, HSP90AA1, TNF, IL1B, MYC, and CASP3. Additionally, the autophagy pathway was found to be one of the main pathways through which XJR intervenes in HCC. The increased quantity of autophagosomes and autolysosomes, the overexpression of Beclin1 and LC3A/B-II proteins, and the downregulation of P62 all suggest that XJR stimulated autophagy in HCC cells. Functional tests employing pathway-specific activators and inhibitors and siRNA-based knockdown demonstrated that XJR promoted autophagy by blocking AKT/mTOR signaling. Furthermore, XJR reduced the viability of HCC cells and promoted apoptosis by upregulating apoptosis proteins. Autophagy inhibitors and Beclin1 silencing reversed these effects. Research conducted in vivo showed that XJR activated autophagy through the AKT/mTOR axis, thereby markedly reducing tumor growth and inducing tumor cell demise. CONCLUSIONS These studies show that XJR activates autophagy in both cellular and animal models to induce apoptosis and decrease HCC cell proliferation, as shown by network pharmacology and verification assays. Further, these findings provide experimental evidence that the anti-tumor activity of XJR involves autophagy stimulation.
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Affiliation(s)
- Yi Ji
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
| | - Li Li
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China
| | - Wenting Li
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China
| | - Liu Li
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China
| | - Yanxia Ma
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qingfeng Li
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xi Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
| | - Wenyue Zhao
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, 214071, China
| | - Hengzhou Zhu
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, 214071, China.
| | - Jiege Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.
| | - Mianhua Wu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing, 210023, China.
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Zhu Y, He Y, Gan R. Wnt Signaling in Hepatocellular Carcinoma: Biological Mechanisms and Therapeutic Opportunities. Cells 2024; 13:1990. [PMID: 39682738 PMCID: PMC11640042 DOI: 10.3390/cells13231990] [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: 10/20/2024] [Revised: 11/19/2024] [Accepted: 12/01/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC), characterized by significant morbidity and mortality rates, poses a substantial threat to human health. The expression of ligands and receptors within the classical and non-classical Wnt signaling pathways plays an important role in HCC. The Wnt signaling pathway is essential for regulating multiple biological processes in HCC, including proliferation, invasion, migration, tumor microenvironment modulation, epithelial-mesenchymal transition (EMT), stem cell characteristics, and autophagy. Molecular agents that specifically target the Wnt signaling pathway have demonstrated significant potential for the treatment of HCC. However, the precise mechanism by which the Wnt signaling pathway interacts with HCC remains unclear. In this paper, we review the alteration of the Wnt signaling pathway in HCC, the mechanism of Wnt pathway action in HCC, and molecular agents targeting the Wnt pathway. This paper provides a theoretical foundation for identifying molecular agents targeting the Wnt pathway in hepatocellular carcinoma.
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Affiliation(s)
| | | | - Runliang Gan
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang 421001, China; (Y.Z.); (Y.H.)
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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Cao Z, Tian K, Ran Y, Zhou H, Zhou L, Ding Y, Tang X. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Front Immunol 2024; 15:1506426. [PMID: 39650649 PMCID: PMC11621085 DOI: 10.3389/fimmu.2024.1506426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
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Affiliation(s)
- Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yincheng Ran
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Haonan Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yana Ding
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiaowei Tang
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
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Liu D, Weng S, Fu C, Guo R, Chen M, Shi B, Weng J. Autophagy in Acute Lung Injury. Cell Biochem Biophys 2024:10.1007/s12013-024-01604-2. [PMID: 39527232 DOI: 10.1007/s12013-024-01604-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Acute lung injury (ALI) is a critical condition marked by rapid-onset respiratory failure due to extensive inflammation and increased pulmonary vascular permeability, often progressing to acute respiratory distress syndrome (ARDS) with high mortality. Autophagy, a cellular degradation process essential for removing damaged organelles and proteins, plays a crucial role in regulating lung injury and repair. This review examines the protective role of autophagy in maintaining cellular function and reducing inflammation and oxidative stress in ALI. It underscores the necessity of precise regulation to fully harness the therapeutic potential of autophagy in this context. We summarize the mechanisms by which autophagy influences lung injury and repair, discuss the interplay between autophagy and apoptosis, and examine potential therapeutic strategies, including autophagy inducers, targeted autophagy signaling pathways, antioxidants, anti-inflammatory drugs, gene editing, and stem cell therapy. Understanding the role of autophagy in ALI could lead to novel interventions for improving patient outcomes and reducing mortality rates associated with this severe condition.
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Affiliation(s)
- Danjuan Liu
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China
| | - Shuoyun Weng
- School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China
| | - Chunjin Fu
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China
| | - Rongjie Guo
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China
| | - Min Chen
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China
| | - Bingbing Shi
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China
| | - Junting Weng
- Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China.
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Seydi H, Nouri K, Shokouhian B, Piryaei A, Hassan M, Cordani M, Zarrabi A, Shekari F, Vosough M. MiR-29a-laden extracellular vesicles efficiently induced apoptosis through autophagy blockage in HCC cells. Eur J Pharm Biopharm 2024; 203:114470. [PMID: 39197541 DOI: 10.1016/j.ejpb.2024.114470] [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: 06/12/2024] [Revised: 08/06/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND In spite of significant advancements in theraputic modalities for hepatocellular carcinoma (HCC), there is still a high annual mortality rate with a rising incidence. Major challenges in the HCC clinical managment are related to the development of therapy resistance, and evasion of tumor cells apoptosis which leading unsatisfactory outcomes in HCC patients. Previous investigations have shown that autophagy plays crucial role in contributing to drug resistance development in HCC. Although, miR-29a is known to counteract authophagy, increasing evidence revealed a down-regulation of miR-29a in HCC patients which correlates with poor prognosis. Beside, evidences showed that miR-29a serves as a negative regulator of autophagy in other cancers. In the current study, we aim to investigate the impact of miR-29a on the autophagy and apoptosis in HCC cells using extracellular vesicles (EVs) as a natural delivery system given their potential in the miRNA delivery both in vitro and in vivo. METHOD Human Wharton's Jelly mesenchymal stromal cell-derived extracellular vesicles were lately isolated through 20,000 or 110,000 × g centrifugation (EV20K or EV110K, respectively), characterized by western blot (WB), scanning electron microscopy (SEM), and dynamic light scattering (DLS). miR-29a was subsequently loaded into these EVs and its loading efficiency was evaluated via RT-qPCR. Comprehensive in vitro and in vivo assessments were then performed on Huh-7 and HepG2 cell lines. RESULTS EV20K-miR-29a treatment significantly induces cell apoptosis and reduces both cell proliferation and colony formation in Huh-7 and HepG2 cell lines. In addition, LC3-II/LC3-I ratio was increased while the expression of key autophagy regulators TFEB and ATG9A were downregulated by this treatment. These findings suggest an effective blockade of autophagy by EV20K-miR-29a leading to apoptosis in the HCC cell lines through concomitant targeting of critical mediators within each pathway.
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Affiliation(s)
- Homeyra Seydi
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran 14155-4364, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran
| | - Kosar Nouri
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran 14155-4364, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan; Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India.
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Wang X, Wang ZY, Chen HT, Luo YY, Li SY, Luo XM, Yang JH, Ma YX, Jin XB, Liu J, Wang ZM. SZ-685C inhibits the growth of non-functioning pituitary adenoma by down-regulating miR-340-3p and inducing autophagy. Heliyon 2024; 10:e37230. [PMID: 39286117 PMCID: PMC11402753 DOI: 10.1016/j.heliyon.2024.e37230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024] Open
Abstract
Background SZ-685C, an anthracycline compound derived from the mangrove endophytic fungus Halorosellinia sp. (No. 1403) collected from the South China Sea, has shown strong anticancer activities. Non-functioning pituitary adenomas (NFPAs) are a type of tumor that can be challenging to manage clinically and have a significant unmet medical need. Our research has found that SZ-685C showed an inhibitory effect on the viability, migration ability, and proliferation ability of a human non-functioning pituitary tumor-derived folliculostellate (PDFS) cell line. Methods SZ-685C was prepared and purified from the mangrove endophytic fungus No. 1403. PDFS cells were exposed to SZ-685C, and the effect of SZ-685C on PDFS cells was evaluated. RNA sequencing was used to analyze the miRNA expression profile in PDFS cells of the control group and SZ-685C-treated group. Quantitative polymerase chain reaction (qPCR) was performed to verify the expression of selected miR-340-3p. The effects of SZ-685C on PDFS cells after overexpression of miR-340-3p were evaluated. Dual-luciferase reporter assays showed PPP1CB is a direct target of miR-340-3p. Finally, the action pathway of the selected miR-340-3p was predicted and evaluated through bioinformatics analysis. Results SZ-685C reduced cell viability in PDFS cells, accompanied by inhibition of migration ability and proliferation ability. The IC50 value for 24 h is 9.144 ± 0.991 μM, and for 48 h is 4.635 ± 0.551 μM. SZ-685C increased the protein levels of Beclin 1, the ratio of LC3-II to LC3-I, and LAMP-1, and down-regulated p62. MiRNA sequencing and further validation showed that miR-340-3p significantly decreased in PDFS cells treated with SZ-685C. After overexpression of miR-340-3p, the inhibition of viability, migration ability, proliferation ability, and autophagy-promoting effect of SZ-685C on PDFS cells were weakened. SZ-685C caused a decrease in PPP1CB expression and activation of the ERK pathway in PDFS cells, and this trend was reversed after overexpression of miR-340-3p. Conclusions SZ-685C downregulates the expression of miR-340-3p in PDFS cells, thereby reducing the expression of PPP1CB and activating the ERK pathway to promote autophagic cell death, leading to inhibition of PDFS cell growth.
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Affiliation(s)
- Xin Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Zhong-Yu Wang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Hui-Tong Chen
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yu-You Luo
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Si-Yuan Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xiong-Ming Luo
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jun-Hua Yang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yu-Xin Ma
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Xiao-Bao Jin
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
- Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Jing Liu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Zong-Ming Wang
- Pituitary Tumor Center, Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
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Zdanowicz A, Grosicka-Maciąg E. The Interplay between Autophagy and Mitochondria in Cancer. Int J Mol Sci 2024; 25:9143. [PMID: 39273093 PMCID: PMC11395105 DOI: 10.3390/ijms25179143] [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: 07/15/2024] [Revised: 08/16/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Besides producing cellular energy, mitochondria are crucial in controlling oxidative stress and modulating cellular metabolism, particularly under stressful conditions. A key aspect of this regulatory role involves the recycling process of autophagy, which helps to sustain energy homeostasis. Autophagy, a lysosome-dependent degradation pathway, plays a fundamental role in maintaining cellular homeostasis by degrading damaged organelles and misfolded proteins. In the context of tumor formation, autophagy significantly influences cancer metabolism and chemotherapy resistance, contributing to both tumor suppression and surveillance. This review focuses on the relationship between mitochondria and autophagy, specifically in the context of cancer progression. Investigating the interaction between autophagy and mitochondria reveals new possibilities for cancer treatments and may result in the development of more effective therapies targeting mitochondria, which could have significant implications for cancer treatment. Additionally, this review highlights the increasing understanding of autophagy's role in tumor development, with a focus on modulating mitochondrial function and autophagy in both pre-clinical and clinical cancer research. It also explores the potential for developing more-targeted and personalized therapies by investigating autophagy-related biomarkers.
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Affiliation(s)
- Aleksandra Zdanowicz
- Department of Biochemistry, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Zwirki i Wigury 81 Str., 02-091 Warsaw, Poland
| | - Emilia Grosicka-Maciąg
- Department of Biochemistry and Laboratory Diagnostic, Collegium Medicum Cardinal Stefan Wyszyński University, Kazimierza Wóycickiego 1 Str., 01-938 Warsaw, Poland
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Xiao X, Gao C. Saikosaponins Targeting Programmed Cell Death as Anticancer Agents: Mechanisms and Future Perspectives. Drug Des Devel Ther 2024; 18:3697-3714. [PMID: 39185081 PMCID: PMC11345020 DOI: 10.2147/dddt.s470455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 08/13/2024] [Indexed: 08/27/2024] Open
Abstract
Saikosaponins (SS), which are major bioactive compounds in Radix Bupleuri, have long been used clinically for multicomponent, multitarget, and multipathway therapeutic strategies. Programmed cell death (PCD) induction is among the multiple mechanisms of SS and mediates the anticancer efficacy of this drug family. Although SS show promise for anticancer therapy, the available data to explain how SS mediate their key anticancer effects through PCD (apoptosis, autophagy, ferroptosis, and pyroptosis) remain limited and piecemeal. This review offers an extensive analysis of the key pathways and mechanisms involved in PCD and explores the importance of SS in cancer. We believe that high-quality clinical trials and a deeper understanding of the pharmacological targets involved in the signalling cascades that govern tumour initiation and progression are needed to facilitate the development of innovative SS-based treatments. Elucidating the specific anticancer pathways activated by SS and further clarifying how comprehensive therapies lead to cross-link among the different types of cell death will inspire the clinical translation of SS as cancer treatments.
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Affiliation(s)
- Xiao Xiao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China
| | - Chunfang Gao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China
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11
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Wei T, Cheng J, Ji Y, Cao X, Ding S, Liu Q, Wang Z. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma. Open Life Sci 2024; 19:20220914. [PMID: 39091624 PMCID: PMC11291770 DOI: 10.1515/biol-2022-0914] [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: 03/04/2024] [Revised: 05/27/2024] [Accepted: 06/04/2024] [Indexed: 08/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly vascularized carcinoma, and targeting its neovascularization represents an effective therapeutic approach. Our previous study demonstrated that the baculovirus-mediated endostatin and angiostatin fusion protein (BDS-hEA) effectively inhibits the angiogenesis of vascular endothelial cells and the growth of HCC tumors. However, the mechanism underlying its anti-angiogenic effect remains unclear. Increasing evidence suggests that autophagy has a significant impact on the function of vascular endothelial cells and response to cancer therapy. Hence, the objective of this research was to investigate the correlation between BDS-hEA-induced angiogenesis inhibition and autophagy, along with potential regulatory mechanisms. Our results demonstrated that BDS-hEA induced autophagy in EA.hy926 cells, as evidenced by the increasing number of autophagosomes and reactive oxygen species, accompanied by an upregulation of Beclin-1, LC3-II/LC3-I, and p62 protein expression. Suppression of autophagy using 3-methyladenine attenuated the functions of BDS-hEA-induced EA.hy926 cells, including the viability, proliferation, invasion, migration, and angiogenesis. Moreover, BDS-hEA induced autophagy by downregulating the expression of CD31, VEGF, and VEGFR2, as well as phosphorylated protein kinase B (p-AKT) and phosphorylated mammalian target of rapamycin (p-mTOR), while concurrently upregulating phosphorylated AMP-activated protein kinase (p-AMPK). The in vivo results further indicated that inhibition of autophagy by chloroquine significantly impeded the ability of BDS-hEA to suppress HCC tumor growth in mice. Mechanistically, BDS-hEA prominently facilitated autophagic apoptosis in tumor tissues and decreased the levels of ki67, CD31, VEGF, MMP-9, p-AKT, and p-mTOR while simultaneously enhancing the p-AMPK expression. In conclusion, our findings suggest that BDS-hEA induces autophagy as a cytotoxic response by modulating the AMPK/AKT/mTOR signaling pathway, thereby exerting anti-angiogenic effects against HCC.
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Affiliation(s)
- Tingting Wei
- Department of Oncology, General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750001, P.R. China
| | - Jiajie Cheng
- School of Pharmacy, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750004, P. R. China
| | - Yonggan Ji
- School of Pharmacy, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750004, P. R. China
| | - Xue Cao
- Department of Oncology, General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750001, P.R. China
| | - Shuqin Ding
- School of Inspection, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750004, P.R. China
| | - Quanxia Liu
- Department of Oncology, General Hospital of Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750001, P.R. China
| | - Zhisheng Wang
- School of Inspection, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750004, P.R. China
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12
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Luo S, Luo R, Deng G, Huang F, Lei Z. Programmed cell death, from liver Ischemia-Reperfusion injury perspective: An overview. Heliyon 2024; 10:e32480. [PMID: 39040334 PMCID: PMC11260932 DOI: 10.1016/j.heliyon.2024.e32480] [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: 01/22/2024] [Revised: 05/26/2024] [Accepted: 06/04/2024] [Indexed: 07/24/2024] Open
Abstract
Liver ischemia-reperfusion injury (LIRI) commonly occurs in liver resection, liver transplantation, shock, and other hemorrhagic conditions, resulting in profound local and systemic effects via associated inflammatory responses and hepatic cell death. Hepatocyte death is a significant component of LIRI and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of programmed cell death (PCD), necroptosis, ferroptosis, pyroptosis, autophagy, NETosis, and parthanatos have been shown to be involved in LIRI. Understanding the mechanisms underlying cell death following LIRI is indispensable to mitigating the widespread effects of LIRI. Here, we review the roles of different PCD and discuss potential therapy in LIRI.
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Affiliation(s)
- Shaobin Luo
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Rongkun Luo
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Gang Deng
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Feizhou Huang
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Zhao Lei
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
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13
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Rahman MA, Rakib-Uz-Zaman SM, Chakraborti S, Bhajan SK, Gupta RD, Jalouli M, Parvez MAK, Shaikh MH, Hoque Apu E, Harrath AH, Moon S, Kim B. Advancements in Utilizing Natural Compounds for Modulating Autophagy in Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Cells 2024; 13:1186. [PMID: 39056768 PMCID: PMC11274515 DOI: 10.3390/cells13141186] [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: 04/16/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy.
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Affiliation(s)
- Md Ataur Rahman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - S M Rakib-Uz-Zaman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
- Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Dhaka 1212, Bangladesh
| | - Somdeepa Chakraborti
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
| | - Sujay Kumar Bhajan
- Department of Biotechnology & Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj 8100, Bangladesh;
| | - Rajat Das Gupta
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA;
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia;
| | | | - Mushfiq H. Shaikh
- Department of Otolaryngology-Head & Neck Surgery, Western University, London, ON N6A 4V2, Canada;
| | - Ehsanul Hoque Apu
- Department of Biomedical Sciences, College of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37923, USA;
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN 37752, USA
- Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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14
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Xu J, Chen F, Zhu W, Zhang W. NPC1 promotes autophagy with tumor promotion and acts as a prognostic model for hepatocellular carcinoma. Gene 2024; 897:148050. [PMID: 38042211 DOI: 10.1016/j.gene.2023.148050] [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: 08/16/2023] [Revised: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 12/04/2023]
Abstract
BACKGROUND more and more studies have indicated that autophagy plays a crucial role in hepatocellular carcinoma (HCC) in recent years. Hence, our study aimed to establish a prognostic signature for HCC based on autophagy-related genes (ARGs) in order to predict the prognosis of HCC. METHODS All original gene-expression data and clinical information were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). ARGs were obtained from the Human Autophagy Database (HADb). Univariate Cox regression analysis, Least absolute shrinkage and selection operator (LASSO) and Principal Component Analysis (PCA) analysis were performed to identify and validate the validity and reliability of our eight-gene signature, Gene Set Enrichment Analysis (GSEA) was used to perform enrichment analysis by comparing high-risk and low-risk groups in KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) gene sets. Finally, we verified the gene (NPC1) by functional experiments in vitro and in vivo. RESULTS 8 ARGs were identified for establishing an eight-gene signature. Then, we validated our eight-gene signature in training, internal, external, and entire testing cohorts. Besides, we also explored the relationships between the eight-gene signature and immune infiltration or immune checkpoints. We also identified NPC1 was closely related to Activated CD4 T cell and Type I IFN Response, and higher expressed level of HCC patients was more sensitive to CTLA4 and TNFRSF9 immune checkpoint inhibitors. NPC1 is highly expressed in HCC cells and tumor tissues, which promotes the proliferation, migration, and invasion of tumor cells by activating autophagy.. CONCLUSION 8 ARGs were used to establish a gene signature to predict the prognosis of HCC. we inferred that NPC1 can promote late autophagy, it could be a future novel therapeutic target of HCC.
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Affiliation(s)
- Jian Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
| | - Fei Chen
- Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
| | - Wenjie Zhu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Wei Zhang
- Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
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15
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Shojaeian A, Nakhaie M, Amjad ZS, Boroujeni AK, Shokri S, Mahmoudvand S. Leveraging metformin to combat hepatocellular carcinoma: its therapeutic promise against hepatitis viral infections. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2023.147] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis ), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
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16
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Zhen JB, Wang RB, Zhang YH, Sun F, Lin LH, Li ZX, Han Y, Lu YX. Effects of Trichinella spiralis and its serine protease inhibitors on autophagy of host small intestinal cells. Infect Immun 2023; 91:e0010323. [PMID: 37874164 PMCID: PMC10652968 DOI: 10.1128/iai.00103-23] [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: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 10/25/2023] Open
Abstract
In eukaryotes, autophagy is induced as an innate defense mechanism against pathogenic microorganisms by self-degradation. Although trichinellosis is a foodborne zoonotic disease, there are few reports on the interplay between Trichinella spiralissurvival strategies and autophagy-mediated host defense. Therefore, this study focused on the association between T. spiralis and autophagy of host small intestinal cells. In this study, the autophagy-related indexes of host small intestinal cells after T. spiralis infection were detected using transmission electron microscopy, hematoxylin and eosin staining, immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting. The results showed that autophagosomes and autolysosomes were formed in small intestinal cells, intestinal villi appeared edema, epithelial compactness was decreased, microtubule-associated protein 1A/1B-light chain 3B (LC3B) was expressed in lamina propria stromal cells of small intestine, and the expression of autophagy-related genes and proteins was changed significantly, indicating that T. spiralis induced autophagy of host small intestinal cells. Then, the effect of T. spiralis on autophagy-related pathways was explored by Western blotting. The results showed that the expression of autophagy-related pathway proteins was changed, indicating that T. spiralis regulated autophagy by affecting autophagy-related pathways. Finally, the roles of T. spiralis serine protease inhibitors (TsSPIs), such as T. spiralis Kazal-type SPI (TsKaSPI) and T. spiralis Serpin-type SPI (TsAdSPI), were further discussed in vitro and in vivo experiments. The results revealed that TsSPIs induced autophagy by influencing autophagy-related pathways, and TsAdSPI has more advantages. Overall, our results indicated that T. spiralis induced autophagy of host small intestinal cells, and its TsSPIs play an important role in enhancing autophagy flux by affecting autophagy-related pathways. These findings lay a foundation for further exploring the pathogenesis of intestinal dysfunction of host after T. spiralis infection, and also provide some experimental and theoretical basis for the prevention and treatment of trichinellosis.
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Affiliation(s)
- Jing-Bo Zhen
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Rui-Biao Wang
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Yu-Heng Zhang
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Feng Sun
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Li-Hao Lin
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Zhi-Xin Li
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Yang Han
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Yi-Xin Lu
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Piekuś-Słomka N, Mocan LP, Shkreli R, Grapă C, Denkiewicz K, Wesolowska O, Kornek M, Spârchez Z, Słomka A, Crăciun R, Mocan T. Don't Judge a Book by Its Cover: The Role of Statins in Liver Cancer. Cancers (Basel) 2023; 15:5100. [PMID: 37894467 PMCID: PMC10605163 DOI: 10.3390/cancers15205100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin's type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.
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Affiliation(s)
- Natalia Piekuś-Słomka
- Department of Inorganic and Analytical Chemistry, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Jurasza 2, 85-089 Bydgoszcz, Poland;
| | - Lavinia Patricia Mocan
- Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Rezarta Shkreli
- Department of Pharmacy, Faculty of Medical Sciences, Aldent University, 1001-1028 Tirana, Albania;
| | - Cristiana Grapă
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania;
| | - Kinga Denkiewicz
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Oliwia Wesolowska
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany;
| | - Zeno Spârchez
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Rareș Crăciun
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Tudor Mocan
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- UBBMed Department, Babeș-Bolyai University, 400349 Cluj-Napoca, Romania
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Bi S, Zhang Y, Zhou J, Yao Y, Wang J, Fang M, Li B, Wu C, Ren C. miR-210 promotes hepatocellular carcinoma progression by modulating macrophage autophagy through PI3K/AKT/mTOR signaling. Biochem Biophys Res Commun 2023; 662:47-57. [PMID: 37099810 DOI: 10.1016/j.bbrc.2023.04.055] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) play an important role in tumor development. Increasing research suggests that miR-210 may promote the progression of tumor virulence, but whether its pro-carcinogenic effect in primary hepatocellular carcinoma (HCC) is via an action on M2 macrophages has not been examined. METHODS Differentiation of THP-1 monocytes into M2-polarized macrophages was induced with phorbol myristate acetate (PMA) and IL-4, IL-13. M2 macrophages were transfected with miR-210 mimics or miR-210 inhibitors. Flow cytometry was used to identify macrophage-related markers and apoptosis levels. The autophagy level of M2 macrophages, expression of PI3K/AKT/mTOR signaling pathway-related mRNAs and protein were detected by qRT-PCR and Western blot. HepG2 and MHCC-97H HCC cell lines were cultured with M2 macrophages conditioned medium to explore the effects of M2 macrophage-derived miR-210 on the proliferation, migration, invasion and apoptosis of HCC cells. RESULTS qRT-PCR showed increased expression of miR-210 in M2 macrophages. Autophagy-related gene and protein expression was enhanced in M2 macrophages transfected with miR-210 mimics, while apoptosis-related proteins were decreased. MDC staining and transmission electron microscopy observed the accumulation of MDC-labeled vesicles and autophagosomes in M2 macrophages in the miR-210 mimic group. The expression of PI3K/AKT/mTOR signaling pathway in M2 macrophages was reduced in miR-210 mimic group. HCC cells co-cultured with M2 macrophages transfected with miR-210 mimics exhibited enhanced proliferation and invasive ability as compared to the control group, while apoptosis levels were reduced. Moreover, promoting or inhibiting autophagy could enhance or abolish the above observed biological effects, respectively. CONCLUSIONS miR-210 can promote autophagy of M2 macrophages via PI3K/AKT/mTOR signaling pathway. M2 macrophage-derived miR-210 promotes the malignant progression of HCC via autophagy, suggesting that macrophage autophagy may serve as a new therapeutic target for HCC, and targeting miR-210 may reset the effect of M2 macrophages on HCC.
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Affiliation(s)
- Shumin Bi
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Yidan Zhang
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Jia Zhou
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Yuanyuan Yao
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Jiadong Wang
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Miaomiao Fang
- School of Nursing, Anhui Medical University, Hefei, Anhui, PR China
| | - Baozhu Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, PR China
| | - Changhao Wu
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
| | - Chunxia Ren
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, PR China.
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Papadakos SP, Ferraro D, Carbone G, Frampton AE, Vennarecci G, Kykalos S, Schizas D, Theocharis S, Machairas N. The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy? Cancers (Basel) 2023; 15:3161. [PMID: 37370771 PMCID: PMC10295995 DOI: 10.3390/cancers15123161] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/05/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Daniele Ferraro
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Gabriele Carbone
- Department of General Surgery and Organ Transplantation, University of Rome “Sapienza”, 00161 Rome, Italy;
| | - Adam Enver Frampton
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK;
- Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, UK
- HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford GU2 7XX, UK
| | - Giovanni Vennarecci
- HPB Surgery and Liver Transplant Unit, AORN A. Cardarelli, 80131 Naples, Italy; (D.F.); (G.V.)
| | - Stylianos Kykalos
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
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21
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Seydi H, Nouri K, Rezaei N, Tamimi A, Hassan M, Mirzaei H, Vosough M. Autophagy orchestrates resistance in hepatocellular carcinoma cells. Biomed Pharmacother 2023; 161:114487. [PMID: 36963361 DOI: 10.1016/j.biopha.2023.114487] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/26/2023] Open
Abstract
Treatment resistance is one of the major barriers for therapeutic strategies in hepatocellular carcinoma (HCC). Many studies have indicated that chemotherapy and radiotherapy induce autophagy machinery (cell protective autophagy) in HCC cells. In addition, many experiments report a remarkable crosstalk between treatment resistance and autophagy pathways. Thus, autophagy could be one of the key factors enabling tumor cells to hinder induced cell death after medical interventions. Therefore, extensive research on the molecular pathways involved in resistance induction and autophagy have been conducted to achieve the desired therapeutic response. The key molecular pathways related to the therapy resistance are TGF-β, MAPK, NRF2, NF-κB, and non-coding RNAs. In addition, EMT, drug transports, apoptosis evasion, DNA repair, cancer stem cells, and hypoxia could have considerable impact on the hepatoma cell's response to therapies. These mechanisms protect tumor cells against various treatments and many studies have shown that each of them is connected to the molecular pathways of autophagy induction in HCC. Hence, autophagy inhibition may be an effective strategy to improve therapeutic outcome in HCC patients. In this review, we further highlight how autophagy leads to poor response during treatment through a complex molecular network and how it enhances resistance in primary liver cancer. We propose that combinational regimens of approved HCC therapeutic protocols plus autophagy inhibitors may overcome drug resistance in HCC therapy.
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Affiliation(s)
- Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Kosar Nouri
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Niloufar Rezaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Department of Biotechnology, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Islamic Republic of Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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22
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Yin Y, Jiang H, Wang Y, Zhang L, Sun C, Xie P, Zheng K, Wang S, Yang Q. Self-Assembled Nanodelivery System with Rapamycin and Curcumin for Combined Photo-Chemotherapy of Breast Cancer. Pharmaceutics 2023; 15:pharmaceutics15030849. [PMID: 36986711 PMCID: PMC10058775 DOI: 10.3390/pharmaceutics15030849] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Nanodelivery systems combining photothermal therapy (PTT) and chemotherapy (CT), have been widely used to improve the efficacy and biosafety of chemotherapeutic agents in cancer. In this work, we constructed a self-assembled nanodelivery system, formed by the assembling of photosensitizer (IR820), rapamycin (RAPA), and curcumin (CUR) into IR820-RAPA/CUR NPs, to realize photothermal therapy and chemotherapy for breast cancer. The IR820-RAPA/CUR NPs displayed a regular sphere, with a narrow particle size distribution, a high drug loading capacity, and good stability and pH response. Compared with free RAPA or free CUR, the nanoparticles showed a superior inhibitory effect on 4T1 cells in vitro. The IR820-RAPA/CUR NP treatment displayed an enhanced inhibitory effect on tumor growth in 4T1 tumor-bearing mice, compared to free drugs in vivo. In addition, PTT could provide mild hyperthermia (46.0 °C) for 4T1 tumor-bearing mice, and basically achieve tumor ablation, which is beneficial to improving the efficacy of chemotherapeutic drugs and avoiding damage to the surrounding normal tissue. The self-assembled nanodelivery system provides a promising strategy for coordinating photothermal therapy and chemotherapy to treat breast cancer.
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Affiliation(s)
- Yanlong Yin
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
| | - Hong Jiang
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
| | - Yue Wang
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
| | - Longyao Zhang
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
| | - Chunyan Sun
- School of Bioscience and Technology, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu 610500, China
| | - Pan Xie
- School of Bioscience and Technology, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu 610500, China
| | - Kun Zheng
- School of Bioscience and Technology, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu 610500, China
| | - Shaoqing Wang
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
- Correspondence: or (S.W.); or (Q.Y.)
| | - Qian Yang
- The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Center of Scientific Research, Chengdu Medical College, Chengdu 610500, China
- Correspondence: or (S.W.); or (Q.Y.)
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23
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Huang J, Xu S, Yu Z, Zheng Y, Yang B, Ou Q. ATP13A2 is a Prognostic Biomarker and Correlates with Immune Infiltrates in Hepatocellular Carcinoma. J Gastrointest Surg 2023; 27:56-66. [PMID: 36127552 DOI: 10.1007/s11605-021-05099-7] [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: 04/13/2021] [Accepted: 07/17/2021] [Indexed: 02/01/2023]
Abstract
PURPOSE To explore the expression and role of ATPase cation transporting 13A2 (ATP13A2) on hepatocellular carcinoma (HCC) progression and prognosis. METHODS The level of ATP13A2 in 63 HCC tissues was evaluated by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. Then, the prognostic value of ATP13A2 for HCC was explored. GO and KEGG pathway enrichments were performed to predict ATP13A2-mediated biological functions. Besides, the correlations between ATP13A2 and key regulators involved in cell cycle and metastasis, the status of different tumor-infiltrating immune cells was investigated. RESULTS ATP13A2 was frequently upregulated in 63 HCC tissues relatively to matched non-tumor tissues. The level of ATP13A2 significantly correlated with tumor stage and tumor grade. HCC patients with higher levels of ATP13A2 had a worse prognosis. Moreover, multivariate survival analysis supported ATP13A2 to be an independent prognostic factor for HCC. GO and KEGG analysis indicated a potential role of ATP13A2 on regulating cell cycle, metastasis, and immune infiltrates. Especially, the level of ATP13A2 was positively correlated with CCNB1, CCND3, CDC25B, CDK4, Vimentin, MMP9, MMP14, and LMNB2. A positive correlation was noticed between ATP13A2 and infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, dendritic cells, monocytes, M2 macrophages, and exhausted T cells in HCC. CONCLUSION Upregulation of ATP13A2 is a common feature as well as an independent prognostic biomarker for HCC. ATP13A2 are associated with key regulators involved in cell cycle, metastasis, and immune infiltrates in HCC, and may act as a potential immunotherapy target for HCC.
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Affiliation(s)
- Jinlan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Gene Diagnosis Research Center, Fujian medical University, Fuzhou, 350005, Fujian Province, China
| | - Siyi Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Zhou Yu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Gene Diagnosis Research Center, Fujian medical University, Fuzhou, 350005, Fujian Province, China
| | - Yansong Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Bin Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian Province, China
- Gene Diagnosis Research Center, Fujian medical University, Fuzhou, 350005, Fujian Province, China
| | - Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China.
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian Province, China.
- Gene Diagnosis Research Center, Fujian medical University, Fuzhou, 350005, Fujian Province, China.
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24
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Zhang SR, Li J, Chen JX, Chen G, Chen JY, Fu HW, Zhou B. SMC4 enhances the chemoresistance of hepatoma cells by promoting autophagy. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1308. [PMID: 36660610 PMCID: PMC9843382 DOI: 10.21037/atm-22-3623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/06/2022] [Indexed: 01/22/2023]
Abstract
Background Drug resistance is a major contributing factor to chemotherapy failure in hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying the chemoresistance of HCC remains unknown. Methods HepG2 cells were incubated with different concentrations of 5-fluorouracil (5-FU), and the Cell Counting Kit-8 assay was used to test the cell survival rate. The expression level of structural maintenance of chromosome 4 (SMC4) in drug-resistant cells was analyzed by real-time quantitative polymerase chain reaction (PCR) and western blotting. To assess autophagy, immunofluorescence was applied to detect the light chain 3 beta (LC3B) level in HepG2/5-FU cells. To further study the upstream regulation of miR (microRNA)-219/SMC4, a gene chip assay was performed. A luciferase reporter assay was used to determine whether long non-coding RNA-XIST (lncRNA-XIST) functions as a competitive endogenous RNA (ceRNA) for miR-219. Cellular proliferation was evaluated using MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-2,5-di-phenytetrazoliumromide] and colony formation assays, wound healing and invasion assays were performed to study the invasion and migration ability of the cells, and flow cytometry assays were carried out to evaluate cell apoptosis. Results In the present study, we established a drug-resistant hepatoma cell line named HepG2/5-FU. We confirmed that SMC4 may play an important role in hepatoma cell autophagy and could promote autophagy to increase the drug resistance of hepatoma cells. We also demonstrated that lncRNA-XIST may competitively bind to miR-219 by acting as a miRNA sponge, thereby preventing miR-219 from effectively reducing the expression of SMC4 and further affecting the autophagy and drug resistance of hepatoma cells via the adenosine 5'-monophosphate (AMP)-activated protein kinase/mechanistic target of rapamycin (AMPK/mTOR) pathway. Conclusions Our study suggests that SMC4 may be a potential marker of a poor HCC response to chemotherapy and a novel therapeutic target for HCC chemotherapy.
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Affiliation(s)
- Shi-Ran Zhang
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing-Xiang Chen
- Department of Hepatobiliary Surgery, The Ninth People’s Hospital of Chongqing City, Chongqing, China
| | - Geng Chen
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jun-Ying Chen
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hang-Wei Fu
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Bo Zhou
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Koshal P, Matera I, Abruzzese V, Ostuni A, Bisaccia F. The Crosstalk between HepG2 and HMC-III Cells: In Vitro Modulation of Gene Expression with Conditioned Media. Int J Mol Sci 2022; 23:ijms232214443. [PMID: 36430920 PMCID: PMC9696318 DOI: 10.3390/ijms232214443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/02/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Epidemiological studies have postulated an inverse correlation between developing cancer and neurodegeneration. It is known that the secretome plays a vital role in cell-cell communication in health and disease; the microglia is the resident macrophage of the central nervous system which maintains neuronal integrity by adapting as the microenvironment changes. The present study aimed to identify, in a cell model, biomarkers that link neurodegenerative diseases to cancer or vice versa. Real-time PCR and western blot analysis were used to characterize the effects on gene and protein expression of human hepatoblastoma (HepG2) and human microglia (HMC-III) cells after exchanging part of their conditioned medium. Biomarkers of the endoplasmic reticulum, and mitophagy and inflammatory processes were evaluated. In both cell types, we observed the activation of cytoprotective mechanisms against any potential pro-oxidant or pro-inflammatory signals present in secretomes. In contrast, HepG2 but not HMC-III cells seem to trigger autophagic processes following treatment with conditioned medium of microglia, thus suggesting a cell-specific adaptive response.
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26
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Zhao X, Yin S, Shi J, Zheng M, He C, Meng H, Han Y, Chen J, Han J, Yuan Z, Wang Y. The association between several autophagy-related genes and their prognostic values in hepatocellular carcinoma: a study on the foundation of TCGA, GEPIA and HPA databases. Mol Biol Rep 2022; 49:10269-10277. [PMID: 36097121 DOI: 10.1007/s11033-022-07426-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND The purpose of this study was to investigate the relationship between the expression of autophagy-related genes and prognosis in hepatocellular carcinoma (HCC). METHODS AND RESULTS We selected three autophagy-related genes (ATG3, ATG7, and ATG9A) from gene expression data of liver cancer patients in The Cancer Genome Atlas (TCGA) database by Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis, and Gene Set Enrichment Analysis (GSEA). Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were applied to testify the credibility of our results. The expression levels of ATG3, ATG7, and ATG9A were verified by real-time quantitative PCR (RT-qPCR) in normal liver cells (L02) and three HCC cell lines (HepG2, Hep3b, and Li-7). Data analysis results from TCGA showed high ATG3, ATG7, ATG9A expression in HCC tumor tissues. Kaplan-Meier survival analysis showed that the survival rate of the high expression group of ATG3, ATG7, and ATG9A was all significantly lower than the low expression group. GSEA analysis showed that many signaling pathways (such as the regulation of autophagy, glycine serine and threonine metabolism, pathways in cancer, mitogen-activated protein kinase (MAPK) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, as well as P53 signaling pathway) were differentially enriched in HCCs with ATG3, ATG7, and ATG9A expression. GEPIA and RT-qPCR also identified that the mRNA expression level of ATG3, ATG7, and ATG9A in normal liver cells were significantly lower than in HCC cells. High protein expression of ATG3, ATG7, and ATG9A was displayed in HCCs from the HPA database. CONCLUSIONS The ATG3, ATG7, ATG9A might be utilized as prognostic biomarkers for liver cancer.
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Affiliation(s)
- Xueying Zhao
- College of Biological Sciences and Biotechnology, Beijing Forestry University, 100083, Beijing, China
| | - Shangqi Yin
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jingren Shi
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Mei Zheng
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Chaonan He
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Huan Meng
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Ying Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jin Chen
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jinyu Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Zhengrong Yuan
- College of Biological Sciences and Biotechnology, Beijing Forestry University, 100083, Beijing, China.
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China.
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Ning YM, Lin K, Liu XP, Ding Y, Jiang X, Zhang Z, Xuan YT, Dong L, Liu L, Wang F, Zhao Q, Wang HZ, Fang J. NAPSB as a predictive marker for prognosis and therapy associated with an immuno-hot tumor microenvironment in hepatocellular carcinoma. BMC Gastroenterol 2022; 22:392. [PMID: 35987606 PMCID: PMC9392949 DOI: 10.1186/s12876-022-02475-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/04/2022] [Indexed: 11/29/2022] Open
Abstract
Background Napsin B Aspartic Peptidase, Pseudogene (NAPSB) was associated with CD4 + T cell infiltration in pancreatic ductal adenocarcinoma. However, the biological role of NAPSB in hepatocellular carcinoma (HCC) remains to be determined. Methods The expression of NAPSB in HCC as well as its clinicopathological association were analyzed using data from several public datasets. qRT-PCR was used to verify the relative expression of NAPSB in patients with HCC using the Zhongnan cohort. Kaplan–Meier analyses, and univariate and multivariate Cox regression were conducted to determine the prognosis value of NAPSB on patients with HCC. Then enrichment analyses were performed to identify the possible biological functions of NAPSB. Subsequently, the immunological characteristics of NAPSB in the HCC tumor microenvironment (TME) were demonstrated comprehensively. The role of NAPSB in predicting hot tumors and its impact on immunotherapy and chemotherapy responses was also analyzed by bioinformatics methods. Results NAPSB was downregulated in patients with HCC and high NAPSB expression showed an improved survival outcome. Enrichment analyses showed that NAPSB was related to immune activation. NAPSB was positively correlated with immunomodulators, tumor-infiltrating immune cells, T cell inflamed score and cancer-immunity cycle, and highly expressed in immuno-hot tumors. High expression of NAPSB was sensitive to immunotherapy and chemotherapy, possibly due to its association with pyroptosis, apoptosis and necrosis. Conclusions NAPSB was correlated with an immuno-hot and inflamed TME, and tumor cell death. It can be utilized as a promising predictive marker for prognosis and therapy in HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02475-8.
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Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L, Chen Y, Han B. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Ther 2022; 7:286. [PMID: 35963853 PMCID: PMC9376115 DOI: 10.1038/s41392-022-01110-y] [Citation(s) in RCA: 391] [Impact Index Per Article: 130.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 02/07/2023] Open
Abstract
Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
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Affiliation(s)
- Fu Peng
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Minru Liao
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shiou Zhu
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
| | - Yi Chen
- West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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29
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Elhusseiny SM, El-Mahdy TS, Elleboudy NS, Yahia IS, Farag MMS, Ismail NSM, Yassien MA, Aboshanab KM. In vitro Anti SARS-CoV-2 Activity and Docking Analysis of Pleurotus ostreatus, Lentinula edodes and Agaricus bisporus Edible Mushrooms. Infect Drug Resist 2022; 15:3459-3475. [PMID: 35813084 PMCID: PMC9259418 DOI: 10.2147/idr.s362823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/27/2022] [Indexed: 12/15/2022] Open
Affiliation(s)
- Shaza M Elhusseiny
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Cairo, 12566, Egypt
| | - Taghrid S El-Mahdy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Nooran S Elleboudy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Ibrahim S Yahia
- Laboratory of Nano-Smart Materials for Science and Technology (LNSMST), Department of Physics, Faculty of Science, Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Nanoscience Laboratory for Environmental and Bio-Medical Applications (NLEBA), Semiconductor Lab, Metallurgical Lab, Physics Department, Faculty of Education, Ain Shams University, Cairo, Egypt
| | - Mohamed M S Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt
- Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Nasser S M Ismail
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, 11835, Egypt
| | - Mahmoud A Yassien
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Khaled M Aboshanab
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
- Correspondence: Khaled M Aboshanab, Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbassia, Cairo, 11566, Egypt, Tel +20 1-0075-82620, Fax +20 224051107, Email
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miR-214 Modulates the Growth and Migration of Oral Cancer before and after Chemotherapy through Mediating ULK1. J Immunol Res 2022; 2022:4589182. [PMID: 35692501 PMCID: PMC9184158 DOI: 10.1155/2022/4589182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/07/2022] [Accepted: 05/13/2022] [Indexed: 11/18/2022] Open
Abstract
The role of miRNAs as crucial components in carcinogenesis has been well documented. However, whether and how miR-214 influences oral cancer cells' drug resistance remains to be elucidated, and its downstream targets are still under investigation. Hence, this research is aimed at determining miR-214 and ULK1 expression in oral cancer before and after chemotherapy and their correlations with cancer cell growth. Human oral normal epithelial cells and human tongue squamous cell carcinoma CAL-27 cells were cultured to detect miR-214 and ULK1 levels. It was found that before chemotherapy, miR-214 was higher, while ULK1 was underexpressed in CAL-27 cells, versus normal epithelial cells. After chemotherapy, miR-214 decreased obviously in CAL-27 cells, while ULK1 level increased significantly. In addition, autophagy-related genes (Beclin 1, mTOR, and P53) in CAL-27 cells were found to be significantly inhibited before chemotherapy and were obviously increased after chemotherapy. Moreover, to further determine the impacts of miR-214 and ULK1 on oral cancer cell growth after chemotherapy, the two were overexpressed or silenced in CAL-27 cells after transfection. We found that ULK1 could effectively decrease the activity and invasion of CAL-27 cells and increase their apoptosis level, while miR-214 could antagonize its antitumor effect. Therefore, miR-214 can be used as an early prognostic biomarker for oral cancer, and ULK1 is a new candidate therapeutic target.
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Batool S, Javed MR, Aslam S, Noor F, Javed HMF, Seemab R, Rehman A, Aslam MF, Paray BA, Gulnaz A. Network Pharmacology and Bioinformatics Approach Reveals the Multi-Target Pharmacological Mechanism of Fumaria indica in the Treatment of Liver Cancer. Pharmaceuticals (Basel) 2022; 15:ph15060654. [PMID: 35745580 PMCID: PMC9229061 DOI: 10.3390/ph15060654] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/04/2022] [Accepted: 05/16/2022] [Indexed: 12/13/2022] Open
Abstract
Liver cancer (LC), a frequently occurring cancer, has become the fourth leading cause of cancer mortality. The small number of reported data and diverse spectra of pathophysiological mechanisms of liver cancer make it a challenging task and a serious economic burden in health care management. Fumaria indica is a herbaceous annual plant used in various regions of Asia to treat a variety of ailments, including liver cancer. Several in vitro investigations have revealed the effectiveness of F. indica in the treatment of liver cancer; however, the exact molecular mechanism is still unrevealed. In this study, the network pharmacology technique was utilized to characterize the mechanism of F. indica on liver cancer. Furthermore, we analyzed the active ingredient-target-pathway network and uncovered that Fumaridine, Lastourvilline, N-feruloyl tyramine, and Cryptopine conclusively contributed to the development of liver cancer by affecting the MTOR, MAPK3, PIK3R1, and EGFR gene. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. The results of molecular docking predicted that several key targets of liver cancer (along with MTOR, EGFR, MAPK3, and PIK3R1) bind stably with the corresponding active ingredient of F. indica. We concluded through network pharmacology methods that multiple biological processes and signaling pathways involved in F. indica exerted a preventing effect in the treatment of liver cancer. The molecular docking results also provide us with sound direction for further experiments. In the framework of this study, network pharmacology integrated with docking analysis revealed that F. indica exerted a promising preventive effect on liver cancer by acting on liver cancer-associated signaling pathways. This enables us to understand the biological mechanism of the anti liver cancer activity of F. indica.
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Affiliation(s)
- Sara Batool
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Muhammad Rizwan Javed
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
- Correspondence: (M.R.J.); (S.A.); Tel.: +92-(0)301-6012931 (M.R.J.); +92-(0)312-1759482 (S.A.)
| | - Sidra Aslam
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
- Correspondence: (M.R.J.); (S.A.); Tel.: +92-(0)301-6012931 (M.R.J.); +92-(0)312-1759482 (S.A.)
| | - Fatima Noor
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | | | - Riffat Seemab
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Abdur Rehman
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Muhammad Farhan Aslam
- School of Biological Sciences, University of Edinburgh, Edinburgh P.O. Box EH9 3FF, UK;
| | - Bilal Ahamad Paray
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
| | - Aneela Gulnaz
- College of Pharmacy, Woosuk University, Wanju-gun 55338, Korea;
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Hou Q, Zhang K, Chen S, Chen J, Zhang Y, Gong N, Guo W, Fang C, Wang L, Jiang J, Dou J, Liang X, Yu J, Liang P. Physical & Chemical Microwave Ablation (MWA) Enabled by Nonionic MWA Nanosensitizers Repress Incomplete MWA-Arised Liver Tumor Recurrence. ACS NANO 2022; 16:5704-5718. [PMID: 35352557 DOI: 10.1021/acsnano.1c10714] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Ionic liquid (IL)-loaded or metal ions-enriched nanoparticles have been witnessed to assist microwave ablation (MWA) and heighten heat utilization for tumor treatment, which, however, inevitably brings about cell dys-homeostasis and severely endangers normal cells or tissues. In this report, a nonionic MWA sensitizer that encapsulates ethyl formate (EF) and doxorubicin (DOX) in liposomes (EF-DOX-Lips) was constructed to reinforce MWA and combined therapy against incomplete MWA-induced tumor recurrence. EF in EF-DOX-Lips as the nonionic liquid can perform like IL to accelerate energy transformation from electromagnetic energy to heat for strengthening MWA. More significantly, EF metabolite, that is, ethanol, also enables chemical ablation, which further enhances MWA. As well, the EF gasification-enhanced lipid rupture and cavitation can promote DOX delivery into a liver tumor for magnifying MWA & chemotherapy combined therapy. By virtue of these contributions, this nonionic MWA nanosensitizer exerts robust antitumor effects to inhibit tumor proliferation and angiogenesis for repressing tumor growth and recurrence or metastasis via downregulating the Epha2 gene and unconventional PI3K/Akt & MAPK signal pathways that the incomplete MWA activated, which provides an avenue to elevate an MWA-based antitumor outcome.
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Affiliation(s)
- Qidi Hou
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
- Department of clinical laboratory, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, No. 1 New City Road, Dongguan 523808, P. R. China
| | - Kun Zhang
- Central Laboratory and Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University School of Medicine. No. 301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
| | - Sitong Chen
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
| | - Jie Chen
- Central Laboratory and Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University School of Medicine. No. 301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
| | - Yan Zhang
- Central Laboratory and Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University School of Medicine. No. 301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
| | - Ningqiang Gong
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 ZhongGuanCun BeiYiTiao, Beijing 100190, P. R. China
| | - Weisheng Guo
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 ZhongGuanCun BeiYiTiao, Beijing 100190, P. R. China
| | - Chao Fang
- Central Laboratory and Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University School of Medicine. No. 301 Yan-chang-zhong Road, Shanghai 200072, P. R. China
| | - Luo Wang
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
| | - Jian Jiang
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
| | - Jianping Dou
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
| | - Xingjie Liang
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 ZhongGuanCun BeiYiTiao, Beijing 100190, P. R. China
| | - Jie Yu
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
| | - Ping Liang
- Department of Medical Ultrasound, Fifth Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, P. R. China
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Li G, Song Z, Wu C, Li X, Zhao L, Tong B, Guo Z, Sun M, Zhao J, Zhang H, Jia L, Li S, Wang L. Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma. J Transl Med 2022; 20:47. [PMID: 35090513 PMCID: PMC8800232 DOI: 10.1186/s12967-022-03247-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/24/2022] Open
Abstract
Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.
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Affiliation(s)
- Guoyin Li
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China.,State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.,Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Zewen Song
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Changjing Wu
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - XiaoYan Li
- Department of Blood Transfusion, Shanxi Province People's Hospital, Taiyuan, China
| | - Liping Zhao
- Department of Pathology, Shanxi Province People's Hospital, Taiyuan, China
| | - Binghua Tong
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Zhenni Guo
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Meiqing Sun
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Jin Zhao
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Huina Zhang
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Shengqing Li
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Lei Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China. .,Clinical Medical College, Yangzhou University, Yangzhou, China.
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Baghaei K, Mazhari S, Tokhanbigli S, Parsamanesh G, Alavifard H, Schaafsma D, Ghavami S. Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today 2021; 27:1044-1061. [PMID: 34952225 DOI: 10.1016/j.drudis.2021.12.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/11/2021] [Accepted: 12/17/2021] [Indexed: 11/03/2022]
Abstract
Hepatic fibrosis is a manifestation of different etiologies of liver disease with the involvement of multiple mediators in complex network interactions. Activated hepatic stellate cells (aHSCs) are the central driver of hepatic fibrosis, given their potential to induce connective tissue formation and extracellular matrix (ECM) protein accumulation. Therefore, identifying the cellular and molecular pathways involved in the activation of HSCs is crucial in gaining mechanistic and therapeutic perspectives to more effectively target the disease. In addition to a comprehensive summary of our current understanding of the role of HSCs in liver fibrosis, we also discuss here the proposed therapeutic strategies based on targeting HSCs.
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Affiliation(s)
- Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Sogol Mazhari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Gilda Parsamanesh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | | | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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35
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Sun H, Wei X, Zeng C. Autophagy in Xp11 translocation renal cell carcinoma: from bench to bedside. Mol Cell Biochem 2021; 476:4231-4244. [PMID: 34345999 DOI: 10.1007/s11010-021-04235-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/27/2021] [Indexed: 12/25/2022]
Abstract
Xp11 translocation renal cell carcinoma (tRCC) characterized by the rearrangement of the TFE3 is recently identified as a unique subtype of RCC that urgently requires effective prevention and treatment strategies. Therefore, determining suitable therapeutic targets and fully understanding the biological significance of tRCC is essential. The importance of autophagy is increasingly acknowledged because it shows carcinogenic activity or suppressor effect. Autophagy is a physiological cellular process critical to maintaining cell homeostasis, which is involved in the lysosomal degradation of cytoplasmic organelles and macromolecules via the lysosomal pathway, suggesting that targeting autophagy is a potential therapeutic approach for cancer therapies. However, the underlying mechanism of autophagy in tRCC is still ambiguous. In this review, we summarize the autophagy-related signaling pathways associated with tRCC. Moreover, we examine the roles of autophagy and the immune response in tumorigenesis and investigate how these factors interact to facilitate or prevent tumorigenesis. Besides, we review the findings regarding the treatment of tRCC via induction or inhibition of autophagy. Hopefully, this study will shed some light on the functions and implications of autophagy and emphasize its role as a potential molecular target for therapeutic intervention in tRCC.
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Affiliation(s)
- Huimin Sun
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, 518110, China
| | - Xing Wei
- Department of Nephrology and Rheumatology, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, 518110, China
| | - Changchun Zeng
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, 518110, China.
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36
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Son J, Kim MJ, Lee JS, Kim JY, Chun E, Lee KY. Hepatitis B virus X Protein Promotes Liver Cancer Progression through Autophagy Induction in Response to TLR4 Stimulation. Immune Netw 2021; 21:e37. [PMID: 34796041 PMCID: PMC8568915 DOI: 10.4110/in.2021.21.e37] [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: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus X (HBx) protein has been reported as a key protein regulating the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Recent evidence has shown that HBx is implicated in the activation of autophagy in hepatic cells. Nevertheless, the precise molecular and cellular mechanism by which HBx induces autophagy is still controversial. Herein, we investigated the molecular and cellular mechanism by which HBx is involved in the TRAF6-BECN1-Bcl-2 signaling for the regulation of autophagy in response to TLR4 stimulation, therefore influencing the HCC progression. HBx interacts with BECN1 (Beclin 1) and inhibits the association of the BECN1-Bcl-2 complex, which is known to prevent the assembly of the pre-autophagosomal structure. Furthermore, HBx enhances the interaction between VPS34 and TRAF6-BECN1 complex, increases the ubiquitination of BECN1, and subsequently enhances autophagy induction in response to LPS stimulation. To verify the functional role of HBx in liver cancer progression, we utilized different HCC cell lines, HepG2, SK-Hep-1, and SNU-761. HBx-expressing HepG2 cells exhibited enhanced cell migration, invasion, and cell mobility in response to LPS stimulation compared to those of control HepG2 cells. These results were consistently observed in HBx-expressed SK-Hep-1 and HBx-expressed SNU-761 cells. Taken together, our findings suggest that HBx positively regulates the induction of autophagy through the inhibition of the BECN1-Bcl-2 complex and enhancement of the TRAF6-BECN1-VPS34 complex, leading to enhance liver cancer migration and invasion.
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Affiliation(s)
- Juhee Son
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Mi-Jeong Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Su Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Young Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | | | - Ki-Young Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea
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37
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Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells. Biomedicines 2021; 9:biomedicines9111527. [PMID: 34829756 PMCID: PMC8615277 DOI: 10.3390/biomedicines9111527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/12/2021] [Accepted: 10/20/2021] [Indexed: 12/20/2022] Open
Abstract
Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.
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38
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Fang M, Jin L, Mao W, Jin L, Cai Y, Ma Q, Liu X, Hua J, Zhu J, Fu H, Shou Q. Hirsutella sinensis fungus improves cardiac function in mouse model of heart failure. Biomed Pharmacother 2021; 142:111885. [PMID: 34385104 DOI: 10.1016/j.biopha.2021.111885] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 05/29/2021] [Accepted: 06/28/2021] [Indexed: 12/17/2022] Open
Abstract
Cordyceps sinensis, including Hirsutella sinensis, is a highly valuable traditional Chinese medicine and is used to treat patients with pulmonary heart disease in clinical practice. However, the underlying mechanisms of its effects remain unclear. In this study, a mouse model of heart failure established by non-thoracic, transverse aortic constriction (TAC) was developed to determine the underlying mechanisms of therapeutic effects of Hirsutella sinensis fungus (HSF) powder. The results showed that HSF treatment remarkably ameliorated myocardial hypertrophy, collagen fiber hyperplasia, and cardiac function in mice with heart failure. Using transcriptional and epigenetic analyses, we found that the mechanism of HSF mainly involved a variety of signaling pathways related to myocardial fibrosis and determined that HSF could reduce the levels of TGF-β1 proteins in heart tissue, as well as type I and III collagen levels. These data suggest that HSF alleviates heart failure, inhibits irreversible ventricular remodeling, and improves cardiac function through the regulation of myocardial fibrosis-related signaling pathways, which can provide novel opportunities to improve heart failure therapy.
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Affiliation(s)
- Mingsun Fang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Animal Experimental Research Center/Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
| | - Lushuai Jin
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
| | - Wen Mao
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
| | - Lu Jin
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Provincial Key Laboratory of Sexual function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Yueqin Cai
- Animal Experimental Research Center/Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
| | - Quanxin Ma
- Animal Experimental Research Center/Institute of Comparative Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, PR China
| | - Xia Liu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Provincial Key Laboratory of Sexual function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Junyi Hua
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Provincial Key Laboratory of Sexual function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China
| | - Jiazhen Zhu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China.
| | - Huiying Fu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Provincial Key Laboratory of Sexual function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China.
| | - Qiyang Shou
- The Second Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou 310053, PR China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, PR China; Zhejiang Provincial Key Laboratory of Sexual function of Integrated Traditional Chinese and Western Medicine, Hangzhou 310053, PR China.
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Sun Z, Lu Z, Li R, Shao W, Zheng Y, Shi X, Li Y, Song J. Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Immunoautophagy-Related Genes and Tumor Microenvironment. Int J Gen Med 2021; 14:5461-5473. [PMID: 34526813 PMCID: PMC8436260 DOI: 10.2147/ijgm.s325884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background The aim of this study was to screen and identify immunoautophagy-related genes (IARGs) in HCC patients and clarify their potential prognostic value in HCC patients. Methods Immune-related genes and autophagy-related gene were downloaded from public databases. Cox regression analysis was used to selected several immunoautophagy-related genes to establish a prognostic model, and patients were divided into high- and low-risk groups based on median risk score. We analyzed the overall survival and clinicopathological characteristics between two groups. Meanwhile, internal validation dataset and external ICGC dataset were used to verify robustness of the model. Associations between six immune cells infiltrates and risk score were analyzed. Results A prognostic model was established based on CANX and HDAC1. The prognoses of the high-risk group were worse than low-risk group in both TCGA and ICGC datasets. Multivariate Cox regression analysis showed that risk score was an independent prognostic factor for HCC patients. Results showed that the risk score in young group was higher than elderly group. Patients with poorly differentiated tumor may have high risk score and poor survival. The score was positively correlated with immune cells. Conclusion Our study shows that immunoautophagy-related genes have potential prognostic value for patients with HCC and may provide new information and direction for targeted therapy.
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Affiliation(s)
- Zhen Sun
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.,Graduate School of Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Zhenhua Lu
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China
| | - Rui Li
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.,Graduate School of Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Weiwei Shao
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.,Graduate School of Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Yangyang Zheng
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.,Graduate School of Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Xiaolei Shi
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China
| | - Yao Li
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China
| | - Jinghai Song
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.,Graduate School of Peking Union Medical College, Beijing, 100730, People's Republic of China
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Elhusseiny SM, El-Mahdy TS, Awad MF, Elleboudy NS, Farag MMS, Yassein MA, Aboshanab KM. Proteome Analysis and In Vitro Antiviral, Anticancer and Antioxidant Capacities of the Aqueous Extracts of Lentinula edodes and Pleurotus ostreatus Edible Mushrooms. Molecules 2021; 26:4623. [PMID: 34361776 PMCID: PMC8348442 DOI: 10.3390/molecules26154623] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 12/16/2022] Open
Abstract
In this study, we examined aqueous extracts of the edible mushrooms Pleurotus ostreatus (oyster mushroom) and Lentinula edodes (shiitake mushroom). Proteome analysis was conducted using LC-Triple TOF-MS and showed the expression of 753 proteins by Pleurotus ostreatus, and 432 proteins by Lentinula edodes. Bioactive peptides: Rab GDP dissociation inhibitor, superoxide dismutase, thioredoxin reductase, serine proteinase and lectin, were identified in both mushrooms. The extracts also included promising bioactive compounds including phenolics, flavonoids, vitamins and amino acids. The extracts showed promising antiviral activities, with a selectivity index (SI) of 4.5 for Pleurotus ostreatus against adenovirus (Ad7), and a slight activity for Lentinula edodes against herpes simplex-II (HSV-2). The extracts were not cytotoxic to normal human peripheral blood mononuclear cells (PBMCs). On the contrary, they showed moderate cytotoxicity against various cancer cell lines. Additionally, antioxidant activity was assessed using DPPH radical scavenging, ABTS radical cation scavenging and ORAC assays. The two extracts showed potential antioxidant activities, with the maximum activity seen for Pleurotus ostreatus (IC50 µg/mL) = 39.46 ± 1.27 for DPPH; 11.22 ± 1.81 for ABTS; and 21.40 ± 2.20 for ORAC assays. This study encourages the use of these mushrooms in medicine in the light of their low cytotoxicity on normal PBMCs vis à vis their antiviral, antitumor and antioxidant capabilities.
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Affiliation(s)
- Shaza M. Elhusseiny
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), 4th Industrial Area, 6th of October City, Cairo 2566, Egypt; (S.M.E.); (T.S.E.-M.)
| | - Taghrid S. El-Mahdy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), 4th Industrial Area, 6th of October City, Cairo 2566, Egypt; (S.M.E.); (T.S.E.-M.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
| | - Mohamed F. Awad
- Department of Biology, College of Science, Taif University, Taif 11099, Saudi Arabia;
| | - Nooran S. Elleboudy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Cairo 11566, Egypt; (N.S.E.); (M.A.Y.)
| | - Mohamed M. S. Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt;
| | - Mahmoud A. Yassein
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Cairo 11566, Egypt; (N.S.E.); (M.A.Y.)
| | - Khaled M. Aboshanab
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Cairo 11566, Egypt; (N.S.E.); (M.A.Y.)
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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