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Wang E, Sun S, Li H, Jia Y, Bai Z. HBx/WDR5 enhances IGF-1 transcription in hepatocellular carcinoma cells and promotes recruitment, infiltration, and activity of Treg cells. Immunol Res 2025; 73:69. [PMID: 40199768 PMCID: PMC11978548 DOI: 10.1007/s12026-025-09620-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 03/09/2025] [Indexed: 04/10/2025]
Abstract
HBV X protein (HBx), the smallest open reading frame in the hepatitis B virus (HBV) genome, can promote hepatocellular carcinoma (HCC) tumorigenesis by activating the expression of multiple oncogenes through inducing epigenetic alterations and interacting with the underlying transcriptional machinery. HBV non-infected HepG2 and Huh7 cells were transfected with HBx expression plasmids. The transcriptional, protein expression, and secretion levels of IGF-1 were detected by RT-qPCR, western blot, and ELISA, respectively. ChIP-qPCR was used to analyze the binding proteins on the IGF-1 gene. A co-culture system of HCC and Treg cells was designed using Transwell chambers. IGF-1 mRNA, protein, and secretion levels were increased in HepG2 and Huh7 cells exogenously expressing HBx. HBx was able to enter the nucleus and interact with the enhancer region of the IGF-1 gene. Levels of WDR5 and H3K4me1, which bind to the enhancer region of the IGF-1 gene, were also increased in HepG2 and Huh7 cells ectopically expressing HBx. Knockdown of WDR5 counteracted the upregulation of IGF-1 mRNA and protein levels by HBx. In the cell co-culture system, HBx/IGF-1 signaling in HCC cells promoted Treg cells expansion, IL-10 secretion, and infiltration, which was blocked by the IGF-1R inhibitor picropodophyllin. HBx/WDR5 promoted IGF-1 transcription in HCC cells through enhancers. HBx could promote Treg cell recruitment, infiltration, and activity by enhancing IGF-1 expression. IGF-1/IGF-1R signaling plays an important role in the communication between HCC cells and Treg cells. Targeting WDR or IGF-1/IGF-1R would be beneficial for the treatment of HCC.
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Affiliation(s)
- Erli Wang
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Province Cancer Hospital, Taiyuani, 030000, Shanx, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, 030000, Shanxi, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Xinghualing District, Cancer Hospital Affiliated to Shanxi Medical University, No. 3, Gongren new street, Taiyuan, 030000, Shanxi, China
| | - Shuhua Sun
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Province Cancer Hospital, Taiyuani, 030000, Shanx, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, 030000, Shanxi, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Xinghualing District, Cancer Hospital Affiliated to Shanxi Medical University, No. 3, Gongren new street, Taiyuan, 030000, Shanxi, China
| | - Hui Li
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan, 030000, Shanxi, China
| | - Yi Jia
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Province Cancer Hospital, Taiyuani, 030000, Shanx, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, 030000, Shanxi, China
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Xinghualing District, Cancer Hospital Affiliated to Shanxi Medical University, No. 3, Gongren new street, Taiyuan, 030000, Shanxi, China
| | - Zhe Bai
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Province Cancer Hospital, Taiyuani, 030000, Shanx, China.
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, 030000, Shanxi, China.
- Department of Hepatobiliary, Pancreatic and Gastric Surgery, Xinghualing District, Cancer Hospital Affiliated to Shanxi Medical University, No. 3, Gongren new street, Taiyuan, 030000, Shanxi, China.
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Zhang L, Jing M, Song Q, Ouyang Y, Pang Y, Ye X, Fu Y, Yan W. Role of the m 6A demethylase ALKBH5 in gastrointestinal tract cancer (Review). Int J Mol Med 2025; 55:22. [PMID: 39611478 PMCID: PMC11637504 DOI: 10.3892/ijmm.2024.5463] [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: 09/13/2024] [Accepted: 11/08/2024] [Indexed: 11/30/2024] Open
Abstract
N6‑methyladenosine (m6A) is one of the most universal, abundant and conserved types of internal post‑transcriptional modifications in eukaryotic RNA, and is involved in nuclear RNA export, RNA splicing, mRNA stability, gene expression, microRNA biogenesis and long non‑coding RNA metabolism. AlkB homologue 5 (ALKBH5) acts as a m6A demethylase to regulate a wide variety of biological processes closely associated with tumour progression, tumour metastasis, tumour immunity and tumour drug resistance. ALKBH5 serves a crucial role in human digestive system tumours, mainly through post‑transcriptional regulation of m6A modification. The present review discusses progress in the study of the m6A demethylase ALKBH5 in gastrointestinal tract cancer, summarizes the potential molecular mechanisms of ALKBH5 dysregulation in gastrointestinal tract cancer, and discusses the significance of ALKBH5‑targeted therapy, which may provide novel ideas for future clinical prognosis prediction, biomarker identification and precise treatment.
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Affiliation(s)
- Lumiao Zhang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Mengjia Jing
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Qianben Song
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yiming Ouyang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yingzhi Pang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xilin Ye
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Kaur A, Azeez GA, Thirunagari M, Fatima N, Anand A, Palvia AR, Yu AK. Association of Chronic Hepatitis B With Colorectal Cancer and Its Dual Impact on Colorectal Liver Metastasis: A Narrative Review. Cureus 2024; 16:e76079. [PMID: 39835087 PMCID: PMC11743875 DOI: 10.7759/cureus.76079] [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: 07/28/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Abstract
Viral hepatitis B is infamous for being contracted in young adulthood and adolescence, as high-risk behaviors like unprotected sexual intercourse and intravenous drug abuse are common. Most infections caused by the hepatitis B virus (HBV) are cleared without any long-term sequelae, but some may persist and cause chronic hepatitis B (CHB). This chronicity may produce a state of prolonged inflammation and significantly increase the risk of developing colorectal adenomas (CRA) and colorectal carcinomas (CRC). The aim of this review is to deep-dive into the mechanisms by which CHB may predispose a patient to develop CRA and, more grimly, CRC. It also focuses on studying the influence of CHB on colorectal cancer liver metastases (CRLM). We conducted a comprehensive literature search using databases like PubMed and Google Scholar, focusing on studies that investigate the role of HBV in colorectal carcinogenesis and CRLM rates in patients suffering from CHB. Chronic inflammation, viral protein interactions with tumor suppressor genes, alteration of cellular pathways such as wingless-related integration site (Wnt) signaling, and extrahepatic accumulation of hepatitis B surface antigen (HBsAg) were the key mechanisms identified. Quite peculiarly, CHB, which is thought to increase the risk for CRA, seemed to protect against CRLM probably due to its sclerosing effect on the liver parenchyma and due to certain immune-mediated mechanisms that suppress tumor growth. Nonetheless, high viral count or the presence of hepatitis B envelope antigen (HBeAg) was found to increase the risk for CRLM, potentially due to increased angiogenesis in the liver. These findings provide convincing evidence that enhanced colonoscopic screening and stronger management protocols for patients suffering from it have the potential to reduce the risk of developing CRC and CRLM.
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Affiliation(s)
- Avneet Kaur
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Gibran A Azeez
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mounika Thirunagari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nazeefa Fatima
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abhinav Anand
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aadi R Palvia
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ann Kashmer Yu
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Tu J, Wang B, Wang X, Huo K, Hu W, Zhang R, Li J, Zhu S, Liang Q, Han S. Current status and new directions for hepatocellular carcinoma diagnosis. LIVER RESEARCH 2024; 8:218-236. [PMID: 39958920 PMCID: PMC11771281 DOI: 10.1016/j.livres.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/17/2024] [Accepted: 12/01/2024] [Indexed: 02/18/2025]
Abstract
Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.
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Affiliation(s)
- Jinqi Tu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Bo Wang
- Animal Experimental Center, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Kugeng Huo
- Cyagen Biosciences (Guangzhou) Inc., Guangzhou, Guangdong, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Rongli Zhang
- Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
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Ma M, Yi L, Pei Y, Zhang Q, Tong C, Zhao M, Chen Y, Zhu J, Zhang W, Yao F, Yang P, Zhang P. USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling. Nat Commun 2024; 15:7856. [PMID: 39251623 PMCID: PMC11385750 DOI: 10.1038/s41467-024-52201-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 08/29/2024] [Indexed: 09/11/2024] Open
Abstract
Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.
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Affiliation(s)
- Mengru Ma
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Lian Yi
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Yifei Pei
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Qimin Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Chao Tong
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Manyu Zhao
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Yuanhong Chen
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Jinghan Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Peijing Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Chen Y, Yang X, Feng M, Yu Y, Hu Y, Jiang W. Exosomal miR-223-3p from bone marrow mesenchymal stem cells targets HDAC2 to downregulate STAT3 phosphorylation to alleviate HBx-induced ferroptosis in podocytes. Front Pharmacol 2024; 15:1327149. [PMID: 38444939 PMCID: PMC10912342 DOI: 10.3389/fphar.2024.1327149] [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: 10/24/2023] [Accepted: 02/05/2024] [Indexed: 03/07/2024] Open
Abstract
Background: Hepatitis B virus associated-glomerulonephritis (HBV-GN) is one of the major secondary renal diseases in China, and microRNAs (miRNAs) in bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo) can attenuate HBV-X protein (HBx)-induced ferroptosis in renal podocytes, but the exact mechanism remains unclear. This study aimed to investigate the protective mechanism of miR-223-3p in BMSC-Exo in HBx-induced ferroptosis in podocytes. Methods: The study employed human renal podocyte cells (HPCs), bone marrow-derived mesenchymal stem cells (BMSCs), as well as kidney tissue from C57BL/6 mice and HBx transgenic mice. Initially, the correlation between STAT3 phosphorylation and ferroptosis was authenticated through the administration of signal transducer and activator of transcription 3 (STAT3) phosphorylation inhibitors in both in vivo and in vitro settings. Furthermore, the effect of HDAC2 overexpression on STAT3 phosphorylation was examined. Subsequently, the association between BMSC-Exo carrying miR-223-3p, HDAC2, and the phosphorylation of STAT3 in HPCs ferroptosis and injury induced by HBx was assessed. The interaction between miR-223-3p and HDAC2 was confirmed via RNA immunoprecipitation assay. Various techniques such as cell counting kit-8 assay, western blot, RT-qPCR, immunofluorescence, flow cytometry, lipid peroxidation assay kit, iron assay kit, transmission electron microscopy, and hematoxylin-eosin staining were employed to visualize the extent of HBx-induced podocyte injury and ferroptosis in both in vivo and in vitro. Results: The attenuation of podocyte ferroptosis can be achieved by inhibiting the phosphorylation of STAT3 in podocytes induced by HBx. Conversely, the upregulation of HDAC2 can enhance STAT3 phosphorylation, thereby promoting podocyte ferroptosis. MiR-223-3p was capable of directly exerting negative regulation on HDAC2 expression. BMSC-Exo carrying miR-223-3p can effectively suppress the expression of HDAC2, ultimately leading to reduce HBx-induced ferroptosis in podocytes by targeting HDAC2 with miR-223-3p and downregulating STAT3 phosphorylation. Conclusion: This study evidences the potential of BMSC-Exo mediated delivery of miR-223-3p in mitigating HBx-induced ferroptosis in podocytes, thereby offering a novel therapeutic target and approach for treating HBV-GN and alleviating renal injury.
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Affiliation(s)
| | | | | | | | | | - Wei Jiang
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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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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Ramakrishnan K, Babu S, Shaji V, Soman S, Leelamma A, Rehman N, Raju R. Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:581-597. [PMID: 38064540 DOI: 10.1089/omi.2023.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.
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Affiliation(s)
| | - Sreeranjini Babu
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Vineetha Shaji
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Anila Leelamma
- Department of Biochemistry, NSS College, Nilamel, Kollam, Kerala, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
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9
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Locatelli M, Faure-Dupuy S. Virus hijacking of host epigenetic machinery to impair immune response. J Virol 2023; 97:e0065823. [PMID: 37656959 PMCID: PMC10537592 DOI: 10.1128/jvi.00658-23] [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] [Indexed: 09/03/2023] Open
Abstract
Epigenetic modifications, such as DNA hypermethylation, histone acetylation/methylation, or nucleosome positioning, result in differential gene expression. These modifications can have an impact on various pathways, including host antiviral immune responses. In this review, we summarize the current understanding of epigenetic modifications induced by viruses to counteract host antiviral immune responses, which are crucial for establishing and maintaining infection of viruses. Finally, we provide insights into the potential use of epigenetic modulators in combating viral infections and virus-induced diseases.
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Affiliation(s)
- Maëlle Locatelli
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Suzanne Faure-Dupuy
- Université de Paris Cité, Institut Cochin, Inserm U1016-CNRS UMR8104, Paris, France
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10
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Yedidya Y, Davis D, Drier Y. SARS-CoV-2 infection perturbs enhancer mediated transcriptional regulation of key pathways. PLoS Comput Biol 2023; 19:e1011397. [PMID: 37561814 PMCID: PMC10443870 DOI: 10.1371/journal.pcbi.1011397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 08/22/2023] [Accepted: 07/28/2023] [Indexed: 08/12/2023] Open
Abstract
Despite extensive studies on the effects of SARS-CoV-2 infection, there is still a lack of understanding of the downstream epigenetic and regulatory alterations in infected cells. In this study, we investigated changes in enhancer acetylation in epithelial lung cells infected with SARS-CoV-2 and their influence on transcriptional regulation and pathway activity. To achieve this, we integrated and reanalyzed data of enhancer acetylation, ex-vivo infection and single cell RNA-seq data from human patients. Our findings revealed coordinated changes in enhancers and transcriptional networks. We found that infected cells lose the WT1 transcription factor and demonstrate disruption of WT1-bound enhancers and of their associated target genes. Downstream targets of WT1 are involved in the regulation of the Wnt signaling and the mitogen-activated protein kinase cascade, which indeed exhibit increased activation levels. These findings may provide a potential explanation for the development of pulmonary fibrosis, a lethal complication of COVID-19. Moreover, we revealed over-acetylated enhancers associated with upregulated genes involved in cell adhesion, which could contribute to cell-cell infection of SARS-CoV-2. Furthermore, we demonstrated that enhancers may play a role in the activation of pro-inflammatory cytokines and contribute to excessive inflammation in the lungs, a typical complication of COVID-19. Overall, our analysis provided novel insights into the cell-autonomous dysregulation of enhancer regulation caused by SARS-CoV-2 infection, a step on the path to a deeper molecular understanding of the disease.
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Affiliation(s)
- Yahel Yedidya
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Daniel Davis
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel
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Zhang X, Hu Y, Vandenhoudt RE, Yan C, Marconi VC, Cohen MH, Justice AC, Aouizerat BE, Xu K. Cell-type specific EWAS identifies genes involved in HIV pathogenesis and oncogenesis among people with HIV infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.21.533691. [PMID: 36993343 PMCID: PMC10055405 DOI: 10.1101/2023.03.21.533691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Epigenome-wide association studies (EWAS) of heterogenous blood cells have identified CpG sites associated with chronic HIV infection, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. Applying a computational deconvolution method validated by capture bisulfite DNA methylation sequencing, we conducted a cell type-based EWAS and identified differentially methylated CpG sites specific for chronic HIV infection among five immune cell types in blood: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes in two independent cohorts (N total =1,134). Differentially methylated CpG sites for HIV-infection were highly concordant between the two cohorts. Cell-type level meta-EWAS revealed distinct patterns of HIV-associated differential CpG methylation, where 67% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of HIV-associated CpG sites (N=1,472) compared to any other cell type. Genes harboring statistically significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CX3CR1 in CD4+ T-cells, CCR7 in B cells, IL12R in NK cells, LCK in monocytes). More importantly, HIV-associated CpG sites were overrepresented for hallmark genes involved in cancer pathology ( FDR <0.05) (e.g. BCL family, PRDM16, PDCD1LGD, ESR1, DNMT3A, NOTCH2 ). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis such as Kras-signaling, interferon-α and -γ, TNF-α, inflammatory, and apoptotic pathways. Our findings are novel, uncovering cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding pathogen-induced epigenetic oncogenicity, specifically on HIV and its comorbidity with cancers.
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Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
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Celik-Turgut G, Olmez N, Koc T, Ozgun-Acar O, Semiz A, Dodurga Y, Lale Satiroglu-Tufan N, Sen A. Role of AHR, NF-kB and CYP1A1 crosstalk with the X protein of Hepatitis B virus in hepatocellular carcinoma cells. Gene 2023; 853:147099. [PMID: 36476661 DOI: 10.1016/j.gene.2022.147099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/22/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
In this study, it was aimed to elucidate the interaction between aryl hydrocarbon receptor (AHR), nuclear factor-kappa B (NF-kB), and cytochrome P4501A1 (CYP1A1) with hepatitis B virus X protein (HBX) in a human liver cancer cell line (HepG2) transfected with HBX. First, AHR, NF-kB, and CYP1A1 genes were cloned into the appropriate region of the CheckMate mammalian two-hybrid recipient plasmids using a flexi vector system. Renilla and firefly luciferases were quantified using the dual-luciferase reporter assay system to measure the interactions. Secondly, transient transfections of CYP1A1 and NF-kB (RelA) were performed into HBX-positive and HBX-negative HepG2 cells. The mRNA expression of CYP1A1 and NF-kB genes were confirmed with RT-PCR, and cell viability was measured by WST-1. Further verification was assessed by measuring the activity and protein level of CYP1A1. Additionally, CYP1A1/HBX protein-protein interactions were performed with co-immunoprecipitation, which demonstrated no interaction. These results have clearly shown that the NF-kB and AHR genes interact with HBX without involving CYP1A1 and HBX protein-protein interactions. The present study confirms that AHR and NF-kB interaction plays a role in the HBV mechanism mediated via HBX and coordinating the carcinogenic or inflammatory responses; still, the CYP1A1 gene has no effect on this interaction.
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Affiliation(s)
- Gurbet Celik-Turgut
- Department of Organic Agriculture Management, Pamukkale University, Denizli, Turkey
| | - Nazmiye Olmez
- Departments of Biology, Pamukkale University, Denizli, Turkey
| | - Tugba Koc
- Departments of Biology, Pamukkale University, Denizli, Turkey
| | - Ozden Ozgun-Acar
- Seed Breeding & Genetics Application Research Center, Pamukkale University, Denizli, Turkey
| | - Asli Semiz
- Departments of Biomedical Engineering, Pamukkale University, Denizli, Turkey
| | - Yavuz Dodurga
- Departments of Medical Biology, Pamukkale University, Denizli, Turkey
| | | | - Alaattin Sen
- Departments of Biology, Pamukkale University, Denizli, Turkey; Departments of Molecular Biology and Genetics, Abdullah Gul University, Kayseri, Turkey.
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Glover A, Zhang Z, Shannon-Lowe C. Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis. Front Immunol 2023; 14:1161848. [PMID: 37033972 PMCID: PMC10076641 DOI: 10.3389/fimmu.2023.1161848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/10/2023] [Indexed: 04/11/2023] Open
Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid cells derived from monocyte and granulocyte precursors. They are pathologically expanded in conditions of ongoing inflammation where they function to suppress both innate and adaptive immunity. They are subdivided into three distinct subsets: monocytic (M-) MDSC, polymorphonuclear (or neutrophilic) (PMN-) MDSC and early-stage (e-) MDSC that may exhibit differential function in different pathological scenarios. However, in cancer they are associated with inhibition of the anti-tumour immune response and are universally associated with a poor prognosis. Seven human viruses classified as Group I carcinogenic agents are jointly responsible for nearly one fifth of all human cancers. These viruses represent a large diversity of species, including DNA, RNA and retroviridae. They include the human gammaherpesviruses (Epstein Barr virus (EBV) and Kaposi's Sarcoma-Associated Herpesvirus (KSHV), members of the high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV, HCV), Human T cell leukaemia virus (HTLV-1) and Merkel cell polyomavirus (MCPyV). Each of these viruses encode an array of different oncogenes that perturb numerous cellular pathways that ultimately, over time, lead to cancer. A prerequisite for oncogenesis is therefore establishment of chronic infection whereby the virus persists in the host cells without being eradicated by the antiviral immune response. Although some of the viruses can directly modulate the immune response to enable persistence, a growing body of evidence suggests the immune microenvironment is modulated by expansions of MDSCs, driven by viral persistence and oncogenesis. It is likely these MDSCs play a role in loss of immune recognition and function and it is therefore essential to understand their phenotype and function, particularly given the increasing importance of immunotherapy in the modern arsenal of anti-cancer therapies. This review will discuss the role of MDSCs in viral oncogenesis. In particular we will focus upon the mechanisms thought to drive the MDSC expansions, the subsets expanded and their impact upon the immune microenvironment. Importantly we will explore how MDSCs may modulate current immunotherapies and their impact upon the success of future immune-based therapies.
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15
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Baidya A, Khatun M, Mondal RK, Ghosh S, Chakraborty BC, Mallik S, Ahammed SKM, Chowdhury A, Banerjee S, Datta S. Hepatitis B virus suppresses complement C9 synthesis by limiting the availability of transcription factor USF-1 and inhibits formation of membrane attack complex: implications in disease pathogenesis. J Biomed Sci 2022; 29:97. [PMID: 36376872 PMCID: PMC9664717 DOI: 10.1186/s12929-022-00876-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 10/29/2022] [Indexed: 11/15/2022] Open
Abstract
Background The complement system functions primarily as a first-line host defense against invading microbes, including viruses. However, the interaction of Hepatitis B virus (HBV) with the complement-components during chronic HBV infection remains largely unknown. We investigated the mechanism by which HBV inhibits the formation of cytolytic complement membrane-attack complex (MAC) and studied its impact on MAC-mediated microbicidal activity and disease pathogenesis. Methods Blood/liver tissues were collected from chronically HBV-infected patients and controls. HepG2hNTCP cells were infected with HBV particles and Huh7 cells were transfected with full-length linear HBV-monomer or plasmids containing different HBV-ORFs and expression of complement components or other host genes were evaluated. Additionally, ELISA, Real-time PCR, Western blot, bioinformatics analysis, gene overexpression/knock-down, mutagenesis, chromatin immunoprecipitation, epigenetic studies, immunofluorescence, and quantification of serum HBV-DNA, bacterial-DNA and endotoxin were performed. Results Among the MAC components (C5b-C9), significant reduction was noted in the expression of C9, the major constituent of MAC, in HBV-infected HepG2hNTCP cells and in Huh7 cells transfected with full-length HBV as well as HBX. C9 level was also marked low in sera/liver of chronic hepatitis B (CHB) and Immune-tolerant (IT) patients than inactive carriers and healthy controls. HBX strongly repressed C9-promoter activity in Huh7 cells but CpG-island was not detected in C9-promoter. We identified USF-1 as the key transcription factor that drives C9 expression and demonstrated that HBX-induced hypermethylation of USF-1-promoter is the leading cause of USF-1 downregulation that in turn diminished C9 transcription. Reduced MAC formation and impaired lysis of HBV-transfected Huh7 and bacterial cells were observed following incubation of these cells with C9-deficient CHB sera but was reversed upon C9 supplementation. Significant inverse correlation was noted between C9 concentration and HBV-DNA, bacterial-DNA and endotoxin content in HBV-infected patients. One-year Tenofovir therapy resulted in improvement in C9 level and decline in viral/bacterial/endotoxin load in CHB patients. Conclusion Collectively, HBX suppressed C9 transcription by restricting the availability of USF-1 through hypermethylation of USF-1-promoter and consequently hinder the formation and lytic functions of MAC. Early therapy is needed for both CHB and IT to normalize the aberrant complement profile and contain viral and bacterial infection and limit disease progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00876-1.
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Hepatitis Viruses Control Host Immune Responses by Modifying the Exosomal Biogenesis Pathway and Cargo. Int J Mol Sci 2022; 23:ijms231810862. [PMID: 36142773 PMCID: PMC9505460 DOI: 10.3390/ijms231810862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
The development of smart immune evasion mechanisms is crucial for the establishment of acute and chronic viral hepatitis. Hepatitis is a major health problem worldwide arising from different causes, such as pathogens, metabolic disorders, and xenotoxins, with the five hepatitis viruses A, B, C, D, and E (HAV, HBV, HCV, HDV, and HEV) representing the majority of the cases. Most of the hepatitis viruses are considered enveloped. Recently, it was reported that the non-enveloped HAV and HEV are, in reality, quasi-enveloped viruses exploiting exosomal-like biogenesis mechanisms for budding. Regardless, all hepatitis viruses use exosomes to egress, regulate, and eventually escape from the host immune system, revealing another key function of exosomes apart from their recognised role in intercellular communication. This review will discuss how the hepatitis viruses exploit exosome biogenesis and transport capacity to establish successful infection and spread. Then, we will outline the contribution of exosomes in viral persistence and liver disease progression.
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17
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [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: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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18
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Feitelson MA, Arzumanyan A, Spector I, Medhat A. Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B. Biomedicines 2022; 10:biomedicines10092210. [PMID: 36140311 PMCID: PMC9496119 DOI: 10.3390/biomedicines10092210] [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: 07/22/2022] [Revised: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/20/2022] Open
Abstract
Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.
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Affiliation(s)
- Mark A. Feitelson
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
- Correspondence: ; Tel.: +1-215-204-8434
| | - Alla Arzumanyan
- Room 409 Biolife Building, Department of Biology, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, PA 19122, USA
| | | | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran 1975933411, Iran
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19
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Yoon H, Jang KL. Hepatitis B virus X protein and hepatitis C virus core protein cooperate to repress E-cadherin expression via DNA methylation. Heliyon 2022; 8:e09881. [PMID: 35832344 PMCID: PMC9272347 DOI: 10.1016/j.heliyon.2022.e09881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/12/2021] [Accepted: 06/30/2022] [Indexed: 11/27/2022] Open
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20
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Hepatitis B Virus-Associated Hepatocellular Carcinoma. Viruses 2022; 14:v14050986. [PMID: 35632728 PMCID: PMC9146458 DOI: 10.3390/v14050986] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.
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21
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Liu T, Song C, Zhang Y, Siyin ST, Zhang Q, Song M, Cao L, Shi H. Hepatitis B virus infection and the risk of gastrointestinal cancers among Chinese population: A prospective cohort study. Int J Cancer 2021; 150:1018-1028. [PMID: 34855203 PMCID: PMC9300134 DOI: 10.1002/ijc.33891] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/17/2021] [Accepted: 11/24/2021] [Indexed: 12/24/2022]
Abstract
Our study aims to explore the relationship between chronic hepatitis B virus (HBV) infection and the risk of gastrointestinal (GI) cancers including liver, gastric, gallbladder or extrahepatic bile duct, pancreatic, small intestine, esophageal and colorectal cancer in the Kailuan Cohort study. We prospectively examined the relationship between HBV infection and new‐onset GI cancers among 93 402 participants. Cox proportional hazards regression models, subgroup analyses and competing risk analyses were used to evaluate the association between HBV infection and the risk of new‐onset GI cancers. During a median follow‐up of 13.02 years, 1791 incident GI cancer cases were diagnosed. Compared to HBsAg seronegative participants, a significant positive association between HBV infection and GI cancers was observed in the multivariate‐adjusted models (HR 5.59, 95% CI: 4.84‐6.45). In the site‐specific analyses, participants with HBsAg seropositive exhibited an increased risk of liver cancer (HR = 21.56, 95% CI: 17.32‐26.85), gallbladder or extrahepatic bile duct cancer (HR = 14.89, 95% CI: 10.36‐21.41), colorectal cancer (HR = 1.75, 95% CI: 1.15‐2.96) and pancreatic cancer (HR = 1.86, 95% CI: 1.10‐3.99). After taking death as the competing risk event, the associations of HBV infection with the risk of these cancers were attenuated but remained significant both in the cause‐specific hazards models, the subdistribution proportional hazards models and sensitivity analyses. Our study suggests that HBV infection is associated with the elevated risk of liver cancer and extrahepatic cancer including gallbladder or extrahepatic bile duct, pancreatic and colorectal cancer among adults in Northern China.
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Affiliation(s)
- Tong Liu
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Department of Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Chunhua Song
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Youcheng Zhang
- Department of Hepatobiliary Surgery, The People's Hospital of Liaoning Province, Shenyang, China.,Department of Graduate School, Dalian Medical University, Dalian, China
| | - Sarah Tan Siyin
- Department of General Surgery, Beijing Children's Hospital, National Center for Children's Health, Beijing, China
| | - Qi Zhang
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Department of Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Mengmeng Song
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Department of Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Liying Cao
- Department of Hepatological Surgery, Kailuan General Hospital, Tangshan, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Department of Clinical Nutrition, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
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22
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Medhat A, Arzumanyan A, Feitelson MA. Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma. Oncotarget 2021; 12:2421-2433. [PMID: 34853663 PMCID: PMC8629409 DOI: 10.18632/oncotarget.28077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
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Affiliation(s)
- Arvin Medhat
- Department of Molecular Cell Biology, Azad University, North Unit, Tehran, Iran
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication. Biomedicines 2021; 9:biomedicines9111701. [PMID: 34829930 PMCID: PMC8616016 DOI: 10.3390/biomedicines9111701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 11/16/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) is a viral regulatory and multifunctional protein. It is well-known that the canonical HBx reading frame bears two phylogenetically conserved internal in-frame translational initiation codons at Met2 and Met3, thus possibly generating divergent N-terminal smaller isoforms during translation. Here, we demonstrate that the three distinct HBx isoforms are generated from the ectopically expressed HBV HBx gene, named XF (full-length), XM (medium-length), and XS (short-length); they display different subcellular localizations when expressed individually in cultured hepatoma cells. Particularly, the smallest HBx isoform, XS, displayed a predominantly cytoplasmic localization. To study HBx proteins during viral replication, we performed site-directed mutagenesis to target the individual or combinatorial expression of the HBx isoforms within the HBV viral backbone (full viral genome). Our results indicate that of all HBx isoforms, only the smallest HBx isoform, XS, can restore WT levels of HBV replication, and bind to the viral mini chromosome, thereby establishing an active chromatin state, highlighting its crucial activities during HBV replication. Intriguingly, we found that sequences of HBV HBx genotype H are devoid of the conserved Met3 position, and therefore HBV genotype H infection is naturally silent for the expression of the HBx XS isoform. Finally, we found that the HBx XM (medium-length) isoform shares significant sequence similarity with the N-terminus domain of the COMMD8 protein, a member of the copper metabolism MURR1 domain-containing (COMMD) protein family. This novel finding might facilitate studies on the phylogenetic origin of the HBV X protein. The identification and functional characterization of its isoforms will shift the paradigm by changing the concept of HBx from being a unique, canonical, and multifunctional protein toward the occurrence of different HBx isoforms, carrying out different overlapping functions at different subcellular localizations during HBV genome replication. Significantly, our current work unveils new crucial HBV targets to study for potential antiviral research, and human virus pathogenesis.
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Alqahtani SA, Colombo M. Treatment for Viral Hepatitis as Secondary Prevention for Hepatocellular Carcinoma. Cells 2021; 10:3091. [PMID: 34831314 PMCID: PMC8619578 DOI: 10.3390/cells10113091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with either hepatitis B or C virus (HBV or HCV) are among the most common risk factors for developing hepatocellular carcinoma (HCC). The hepatocarcinogenic potential of these viruses is mediated through a wide range of mechanisms, including the induction of chronic inflammation and oxidative stress and the deregulation of cellular pathways by viral proteins. Over the last decade, effective anti-viral agents have made sustained viral suppression or cure a feasible treatment objective for most chronic HBV/HCV patients. Given the tumorigenic potential of HBV/HCV, it is no surprise that obtaining sustained viral suppression or eradication proves to be effective in preventing HCC. This review summarizes the mechanisms by which HCV and HBV exert their hepatocarcinogenic activity and describes in detail the efficacy of anti-HBV and anti-HCV therapies in terms of HCC prevention. Although these treatments significantly reduce the risk for HCC in patients with chronic viral hepatitis, this risk is not eliminated. Therefore, we evaluate potential strategies to improve these outcomes further and address some of the remaining controversies.
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Affiliation(s)
- Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, USA
- Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
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25
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Liu GZ, Xu XW, Tao SH, Gao MJ, Hou ZH. HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression. J Biomed Sci 2021; 28:67. [PMID: 34615538 PMCID: PMC8495979 DOI: 10.1186/s12929-021-00762-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Background Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Hepatitis B virus (HBV) infection is the major cause of ALF worldwide, however, the underlying mechanism by which HBV infection leads to ALF has not been fully disclosed. Methods D-GalN-induced hepatocyte injury model and LPS/D-GalN-induced ALF mice model were used to investigate the effects of HBV X protein (HBx) in vitro and in vivo, respectively. Cell viability and the levels of Glutathione (GSH), malondialdehyde (MDA) and iron were measured using commercial kits. The expression of ferroptosis-related molecules were detected by qRT-PCR and western blotting. Epigenetic modification and protein interaction were detected by chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (co-IP), respectively. Mouse liver function was assessed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The histological changes in liver tissues were monitored by hematoxylin and eosin (H&E) staining, and SLC7A11 immunoreactivity was assessed by immunohistochemistry (IHC) analysis. Results D-GalN triggered ferroptosis in primary hepatocytes. HBx potentiated D-GalN-induced hepatotoxicity and ferroptosis in vitro, and it suppressed SLC7A11 expression through H3K27me3 modification by EZH2. In addition, EZH2 inhibition or SLC7A11 overexpression attenuated the effects of HBx on D-GalN-induced ferroptosis in primary hepatocytes. The ferroptosis inhibitor ferrostatin-1 (Fer-1) protected against ALF and ferroptosis in vivo. By contrast, HBx exacerbates LPS/D-GalN-induced ALF and ferroptosis in HBx transgenic (HBx-Tg) mice. Conclusion HBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.
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Affiliation(s)
- Guo-Zhen Liu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China
| | - Xu-Wen Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Shu-Hui Tao
- Department of Liver Diseases, Shenzhen Hospital, Southern Medical University, Shenzhen, 518100, Guangdong, China
| | - Ming-Jian Gao
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China
| | - Zhou-Hua Hou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China.
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26
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Li YT, Wu HL, Liu CJ. Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1. Int J Mol Sci 2021; 22:9380. [PMID: 34502289 PMCID: PMC8431721 DOI: 10.3390/ijms22179380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis.
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Affiliation(s)
- Yung-Tsung Li
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Hui-Lin Wu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
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27
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Pietropaolo V, Prezioso C, Moens U. Role of Virus-Induced Host Cell Epigenetic Changes in Cancer. Int J Mol Sci 2021; 22:ijms22158346. [PMID: 34361112 PMCID: PMC8346956 DOI: 10.3390/ijms22158346] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- Correspondence: (V.P.); (U.M.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-Degenerative Pathologies, 00161 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
- Correspondence: (V.P.); (U.M.)
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28
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Qu S, Jin L, Huang H, Lin J, Gao W, Zeng Z. A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis. BMC Cancer 2021; 21:686. [PMID: 34112124 PMCID: PMC8194239 DOI: 10.1186/s12885-021-08449-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. METHODS The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. RESULT ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo. CONCLUSIONS HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.
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Affiliation(s)
- Siming Qu
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Li Jin
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Hanfei Huang
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Jie Lin
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan Province, China
| | - Weiwu Gao
- Institute of Immunology, PLA, Third Military Medical University, 30 Gaotanyan St., District Shapingba, Chongqing, 400038, China.
| | - Zhong Zeng
- Organ Transplantation Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, Yunnan Province, China.
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29
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Dzobo K. The Role of Viruses in Carcinogenesis and Molecular Targeting: From Infection to Being a Component of the Tumor Microenvironment. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:358-371. [PMID: 34037476 DOI: 10.1089/omi.2021.0052] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
About a tenth of all cancers are caused by viruses or associated with viral infection. Recent global events including the coronavirus disease-2019 (COVID-19) pandemic means that human encounter with viruses is increased. Cancer development in individuals with viral infection can take many years after infection, demonstrating that the involvement of viruses in cancer development is a long and complex process. This complexity emanates from individual genetic heterogeneity and the many steps involved in cancer development owing to viruses. The process of tumorigenesis is driven by the complex interaction between several viral factors and host factors leading to the creation of a tumor microenvironment (TME) that is ideal and promotes tumor formation. Viruses associated with human cancers ensure their survival and proliferation through activation of several cellular processes including inflammation, migration, and invasion, resistance to apoptosis and growth suppressors. In addition, most human oncoviruses evade immune detection and can activate signaling cascades including the PI3K-Akt-mTOR, Notch and Wnt pathways associated with enhanced proliferation and angiogenesis. This expert review examines and synthesizes the multiple biological factors related to oncoviruses, and the signaling cascades activated by these viruses contributing to viral oncogenesis. In particular, I examine and review the Epstein-Barr virus, human papillomaviruses, and Kaposi's sarcoma herpes virus in a context of cancer pathogenesis. I conclude with a future outlook on therapeutic targeting of the viruses and their associated oncogenic pathways within the TME. These anticancer strategies can be in the form of, but not limited to, antibodies and inhibitors.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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30
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Guo J, Gao XS. Prediction models for development of hepatocellular carcinoma in chronic hepatitis B patients. World J Clin Cases 2021; 9:3238-3251. [PMID: 34002133 PMCID: PMC8107908 DOI: 10.12998/wjcc.v9.i14.3238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/11/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is a major health problem in Asian-Pacific regions. Antiviral therapy reduces, but does not completely prevent, HCC development. Thus, there is a need for accurate risk prediction to assist prognostication and decisions on the need for antiviral therapy and HCC surveillance. A few risk scores have been developed to predict the occurrence of HCC in CHB patients. Initially, the scores were derived from untreated CHB patients. With the development and extensive clinical application of nucleos(t)ide analog(s) (NA), the number of risk scores based on treated CHB patients has increased gradually. The components included in risk scores may be categorized into host factors and hepatitis B virus factors. Hepatitis activities, hepatitis B virus factors, and even liver fibrosis or cirrhosis are relatively controlled by antiviral therapy. Therefore, variables that are more dynamic during antiviral therapy have since been included in risk scores. However, host factors are more difficult to modify. Most existing scores derived from Asian populations have been confirmed to be accurate in predicting HCC development in CHB patients from Asia, while these scores have not offered excellent predictability in Caucasian patients. These findings support that more relevant variables should be considered to provide individualized predictions that are easily applied to CHB patients of different ethnicities. CHB patients should receive different intensities of HCC surveillance according to their risk category.
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Affiliation(s)
- Jiang Guo
- Department of Interventional Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xue-Song Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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31
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Sekiba K, Otsuka M, Koike K. Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver. Semin Liver Dis 2021; 41:142-149. [PMID: 33984871 DOI: 10.1055/s-0041-1723033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
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Grants
- Japan Agency for Medical Research and Development, AMED JP20fk0210054
- Japan Agency for Medical Research and Development, AMED JP20fk0210080h0001
- Japan Agency for Medical Research and Development, AMED JP20fk0310102
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19H03430
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19J11829
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Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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32
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McBrearty N, Arzumanyan A, Bichenkov E, Merali S, Merali C, Feitelson M. Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice. Neoplasia 2021; 23:529-538. [PMID: 33945993 PMCID: PMC8111251 DOI: 10.1016/j.neo.2021.04.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The HBV encoded oncoprotein, HBx, alters the expression of host genes and the activity of multiple signal transduction pathways that contribute to the pathogenesis of HCC by multiple mechanisms independent of HBV replication. However, it is not clear which pathways are the most relevant therapeutic targets in hepatocarcinogenesis. Short chain fatty acids (SCFAs) have strong anti-inflammatory and anti-neoplastic properties, suggesting that they may block the progression of chronic liver disease (CLD) to HCC, thereby identifying the mechanisms relevant to HCC development. This hypothesis was tested in HBx transgenic (HBxTg) mice fed SCFAs. Groups of HBxTg mice were fed with SCFAs or vehicle from 6 to 9 months of age and then assessed for dysplasia, and from 9 to 12 months of age and then assessed for HCC. Livers from 12 month old mice were then analyzed for changes in gene expression by mass spectrometry-based proteomics. SCFA-fed mice had significantly fewer dysplastic and HCC nodules compared to controls at 9 and 12 months, respectively. Pathway analysis of SCFA-fed mice showed down-regulation of signaling pathways altered by HBx in human CLD and HCC, including those involved in inflammation, phosphatidylinositol 3-kinase, epidermal growth factor, and Ras. SCFA treatment promoted increased expression of the tumor suppressor, disabled homolog 2 (DAB2). DAB2 depresses Ras pathway activity, which is constitutively activated by HBx. SCFAs also reduced cell viability in HBx-transfected cell lines in a dose-dependent manner while the viability of primary human hepatocytes was unaffected. These unique findings demonstrate that SCFAs delay the pathogenesis of CLD and development of HCC, and provide insight into some of the underlying mechanisms that are relevant to pathogenesis in that they are responsive to treatment.
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Affiliation(s)
- Noreen McBrearty
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Eugene Bichenkov
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Salim Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Carmen Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Mark Feitelson
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA.
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33
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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34
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Chai X, Guo J, Dong R, Yang X, Deng C, Wei C, Xu J, Han W, Lu J, Gao C, Gao D, Huang C, Ke A, Li S, Li H, Tian Y, Gu Z, Liu S, Liu H, Chen Q, Liu F, Zhou J, Fan J, Shi G, Wu F, Cai J. Quantitative acetylome analysis reveals histone modifications that may predict prognosis in hepatitis B-related hepatocellular carcinoma. Clin Transl Med 2021; 11:e313. [PMID: 33783990 PMCID: PMC7939233 DOI: 10.1002/ctm2.313] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/20/2022] Open
Abstract
Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.
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Affiliation(s)
- Xiaoqiang Chai
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Jianfei Guo
- Shanghai Center for Plant Stress BiologyCenter for Excellence in Plant Molecular SciencesChinese Academy of SciencesShanghaiChina
- Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of AgricultureAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhenChina
| | - Ruizhao Dong
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Xuan Yang
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Chao Deng
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
- School of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Chuanyuan Wei
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - JiaJie Xu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
- School of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Weiyu Han
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Jiacheng Lu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Chao Gao
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Dongmei Gao
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Cheng Huang
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Aiwu Ke
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Shuangqi Li
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Huanping Li
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Yingming Tian
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Zhongkai Gu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Shuxian Liu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Hang Liu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Qilong Chen
- Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Feng Liu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Jian Zhou
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Jia Fan
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Guoming Shi
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Feizhen Wu
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
| | - Jiabin Cai
- Department of Liver Surgery and Transplantation of Zhongshan Hospital, Liver Cancer Institute of Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Laboratory of epigenetics of Institutes of Biomedical Sciences, Key Laboratory of Birth Defects of Children's HospitalFudan UniversityShanghaiChina
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Lim HC, Gordan JD. Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma. PLoS Comput Biol 2021; 17:e1008699. [PMID: 33561166 PMCID: PMC7909678 DOI: 10.1371/journal.pcbi.1008699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 02/26/2021] [Accepted: 01/13/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse outcomes. Many prior studies of HBV-related HCC have not accounted for potential heterogeneity among HBV-related tumors by assessing whether HBV activity is present in tumor tissue. Here, we measured tumor HBV RNA, a proxy for viral activity, and investigated the association between HBV RNA status and several clinicogenomic characteristics. We obtained clinical, mutation, RNA-Seq and survival data for 439 HCC tumors from The Cancer Genome Atlas and International Cancer Genome Consortium. Tumors were classified as HBV RNA positive if they harbored >1 HBV RNA read per million human reads. We investigated the association between HBV RNA status and nonsynonymous somatic mutations, gene set expression, homologous recombination deficiency (HRD) score and mutation-specific survival. HBV RNA positive status was associated with higher nonsynonymous mutation rates of multiple genes, including TP53 and CDKN2A, while HBV RNA negative status was associated with higher nonsynonymous BAP1 mutation rate. HBV RNA positive status was also associated with increased transcription of genes involved in multiple DNA damage repair pathways, genes upregulated by MYC and mTORC1, and genes overexpressed in several HCC subclasses associated with a proliferative phenotype. Further, HBV RNA positive status was associated with increased three-biomarker HRD score (22.2 for HBV RNA+ vs. 16.0 for HBV RNA-). Finally, HBV RNA status was associated with multiple mutation-specific survival differences, including decreased survival for HBV RNA positive patients with nonsynonymous KEAP1 mutations compared to those without (hazard ratio 4.26). HCC tumors harboring genomic evidence of HBV activity therefore constitute a distinct HCC subset characterized by specific differences in nonsynonymous mutations, gene set expression, three-biomarker HRD score and mutation-specific survival. Hepatocellular carcinoma, the most common type of liver cancer, is the second leading cause of cancer death worldwide and is most commonly caused by hepatitis B virus infection. Currently, scientists have an incomplete understanding of the genomic basis of hepatocellular carcinoma associated with hepatitis B virus infection, because prior studies have been limited by imprecision in assessing hepatitis B virus infection status and heterogeneity in hepatitis B virus activity levels in liver tumors. This has limited scientists’ ability to devise new diagnostic and therapeutic options for hepatocellular carcinoma. In this study, we used computational genomics to directly measure hepatitis B virus RNA levels in a large dataset of hepatocellular carcinoma tumors, and found that tumors with measurable hepatitis B virus RNA levels are associated with a specific set of clinical and genomic characteristics. These characteristics have not previously been reported and harbor implications for future clinical and genomics research in hepatocellular carcinoma, as well as computational genomics efforts in other cancer types.
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Affiliation(s)
- Huat Chye Lim
- Division of Hematology and Oncology, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail: (HCL); (JDG)
| | - John D. Gordan
- Division of Hematology and Oncology, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail: (HCL); (JDG)
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36
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Kabashima A, Shimada S, Shimokawa M, Akiyama Y, Tanabe M, Tanaka S. Molecular and immunological paradigms of hepatocellular carcinoma: Special reference to therapeutic approaches. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:62-75. [PMID: 33259135 DOI: 10.1002/jhbp.874] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/09/2020] [Accepted: 10/11/2020] [Indexed: 12/14/2022]
Abstract
The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular-targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune-checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune-associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune-combination approaches from a molecular pathological point.
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Affiliation(s)
- Ayano Kabashima
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masahiro Shimokawa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Hojati Z, Omidi F, Dehbashi M, Mohammad Soltani B. The Highlighted Roles of Metabolic and Cellular Response to Stress Pathways Engaged in Circulating hsa-miR-494-3p and hsa-miR-661 in Alzheimer's Disease. IRANIAN BIOMEDICAL JOURNAL 2020; 25:62-7. [PMID: 33129241 PMCID: PMC7748118 DOI: 10.29252/ibj.25.1.62] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Background: Among different roles of miRNAs in AD pathogenesis, hsa-miR-494-3p and hsa-miR-661 functions are poorly understood. Methods: To obtain the gene targets, gene networks, gene ontology, and enrichment analysis of the two miRNAs, some web servers were utilized. Furthermore, the expressions of these miRNAs were analyzed by qRT-PCR in 36 blood sera, including 18 Alzheimer’s patients and 18 healthy individuals. Results: The in silico analysis demonstrated the highlighted roles of metabolic and cellular response to stress pathways engaged in circulating hsa-miR-494-3p and hsa-miR-661 in AD. The qRT-PCR analysis showed that the downregulated expression level of hsa-miR-661 was statistically significant (p < 0.05). Also, the ROC curve of hsa-miR-661 displayed the significant AUC (p = 0.01). Conclusion: Based on our findings, the metabolic and cellular responses to stress pathways are closely connected to these two miRNAs functions. Besides, the qRT-PCR and Roc curve determined hsa-miR-661 could be as a biomarker for diagnosis or prognosis of AD patients.
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Affiliation(s)
- Zohreh Hojati
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan 8174673441, Iran
| | - Farzaneh Omidi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Moein Dehbashi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan 8174673441, Iran
| | - Bahram Mohammad Soltani
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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38
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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Niedźwiedzka-Rystwej P, Grywalska E, Hrynkiewicz R, Wołącewicz M, Becht R, Roliński J. The Double-Edged Sword Role of Viruses in Gastric Cancer. Cancers (Basel) 2020; 12:cancers12061680. [PMID: 32599870 PMCID: PMC7352989 DOI: 10.3390/cancers12061680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/14/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and their potential seem to be an important issue. On one hand, several oncogenic viruses have been noticed in the case of gastric cancer, making the positive treatment even more advantageous, but on the other, viruses exist with a potential therapeutic role in this malignancy.
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Affiliation(s)
- Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
- Correspondence:
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Mikołaj Wołącewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Rafał Becht
- Clinical Department of Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University of Szczecin, 70-204 Szczecin, Poland;
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
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Gao W, Jia Z, Tian Y, Yang P, Sun H, Wang C, Ding Y, Zhang M, Zhang Y, Yang D, Tian Z, Zhou J, Ruan Z, Wu Y, Ni B. HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein. Hepatology 2020; 71:1678-1695. [PMID: 31544250 DOI: 10.1002/hep.30947] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 09/09/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Cancer is typically considered as a genetic and epigenetic disease. Although numerous studies have indicated that an aberrant structure, function, or expression level of epigenetic enzymes contribute to many tumor types, precisely how the epigenetic mechanisms are involved in the hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unknown. APPROACH AND RESULTS In this study, we found that the WD repeat domain 5 protein (WDR5)-a core subunit of histone H3 lysine 4 methyltransferase complexes, which catalyze the generation of histone H3 lysine 4 trimethylation (H3K4me3) modification-is highly expressed in HBV-related HCC and promotes HCC development. WDR5 plays a critical role in HBV-driven cell proliferation and tumor growth in mice, and the WDR5-0103 small-molecule inhibitor of WDR5 activity compromises HBV- and hepatitis B x protein (HBx)-driven tumor proliferation. The aberrantly high WDR5 protein level was found to involve HBx through its stabilization of the WDR5 protein by inhibiting the interaction between the damage-specific DNA-binding protein 1/cullin-4 and WDR5, causing decreased ubiquitination of the WDR5 protein. HBx was found to colocalize with WDR5 on chromatin genome wide and promotes genome-wide H3K4me3 modification by means of WDR5. Furthermore, the recruitment of HBx to promoters of target genes relied on its interaction with WDR5 through its α-helix domain. WDR5 was also found to promote HBV transcription through H3K4 modification of covalently closed circular DNA minichromosome, and WDR5-0103 was able to inhibit HBV transcription. Finally, the in vitro and in vivo data further proved that HBx exerted its tumor-promoting function in a WDR5-dependent manner. CONCLUSIONS Our data reveals that WDR5 is a key epigenetic determinant of HBV-induced tumorigenesis and that the HBx-WDR5-H3K4me3 axis may be a potential therapeutic target in HBV-induced liver pathogenesis.
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Affiliation(s)
- Weiwu Gao
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
- Key Laboratory of High Altitude Medicine, PLA, Chongqing, China
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Zhengcai Jia
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yi Tian
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | | | - Hui Sun
- Department of Rheumatology and Immunology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Chenhui Wang
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Yi Ding
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD
- Allen Institute for Brain Science, Seattle, WA
| | - Mengjie Zhang
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China
| | - Yi Zhang
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China
| | - Di Yang
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Zhiqiang Tian
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Jian Zhou
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Zhihua Ruan
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yuzhang Wu
- Institute of Immunology of PLA, Third Military Medical University, Chongqing, China
| | - Bing Ni
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
- Key Laboratory of High Altitude Medicine, PLA, Chongqing, China
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41
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Yu DY. Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein. Lab Anim Res 2020; 36:6. [PMID: 32206612 PMCID: PMC7081669 DOI: 10.1186/s42826-020-00037-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 02/12/2020] [Indexed: 12/16/2022] Open
Abstract
The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11–18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.
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Affiliation(s)
- Dae-Yeul Yu
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 South Korea
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Chronic Hepatitis B Virus Infection Associated with Increased Colorectal Cancer Risk in Taiwanese Population. Viruses 2020; 12:v12010097. [PMID: 31947702 PMCID: PMC7019239 DOI: 10.3390/v12010097] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/07/2020] [Accepted: 01/10/2020] [Indexed: 12/22/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infections and colorectal cancer (CRC) are prevalent in Taiwan. We carried out a population-based case-control study to assess the association between HBV infection and CRC risk. Using the National Health Insurance Research Database of Taiwan, we identified 69,478 newly diagnosed patients with CRC from 2005 to 2011. We further randomly selected 69,478 age- and gender-matched controls without CRC from the same database. Odds ratios (ORs) were calculated to evaluate the association between chronic HBV infection and CRC using a logistic regression analysis. HBV infection was found to be associated with the risk of CRC (OR = 1.27, 95% confidence interval (CI) = 1.20–1.33). This relationship was similar in men and women. Age-specific analysis revealed that the CRC risk associated with HBV decreased with age. The adjusted ORs for patients aged <55, 55–64, and 65–74 years were 1.63 (95% CI = 1.48–1.79), 1.24 (95% CI = 1.13–1.37), and 1.02 (95% = 0.92–1.13), respectively. In conclusion, this study suggests that chronic HBV infection is significantly associated with an increased risk of CRC. Monitoring the risk of CRC development in young patients with HBV infection is crucial.
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Mitochondria ubiquitin ligase, MARCH5 resolves hepatitis B virus X protein aggregates in the liver pathogenesis. Cell Death Dis 2019; 10:938. [PMID: 31819032 PMCID: PMC6901512 DOI: 10.1038/s41419-019-2175-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/26/2019] [Accepted: 11/26/2019] [Indexed: 12/12/2022]
Abstract
Infection of hepatitis B virus (HBV) increase the incidence of chronic liver disease and hepatocellular carcinoma (HCC). The hepatitis B viral x (HBx) protein encoded by the HBV genome contributes to the pathogenesis of HCC and thus, negative regulation of HBx is beneficial for the alleviation of the disease pathogenesis. MARCH5 is a mitochondrial E3 ubiquitin ligase and here, we show that high MARCH5 expression levels are correlated with improved survival in HCC patients. MARCH5 interacts with HBx protein mainly accumulated in mitochondria and targets it for degradation. The N-terminal RING domain of MARCH5 was required for the interaction with HBx, and MARCH5H43W lacking E3 ligase activity failed to reduce HBx protein levels. High expression of HBx results in the formation of protein aggregates in semi-denaturing detergent agarose gels and MARCH5 mediates the elimination of protein aggregates through the proteasome pathway. HBx-induced ROS production, mitophagy, and cyclooxygenase-2 gene expression were suppressed in the presence of high MARCH5 expression. These results suggest MARCH5 as a target for alleviating HBV-mediated liver disease.
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44
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Correlation between Hepatitis B Virus Infection and Colorectal Neoplasia. J Clin Med 2019; 8:jcm8122085. [PMID: 31805669 PMCID: PMC6947584 DOI: 10.3390/jcm8122085] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/09/2019] [Accepted: 11/22/2019] [Indexed: 12/29/2022] Open
Abstract
Background: Data about the association between hepatitis virus infection and colorectal neoplasia (CRN) are extremely limited. We examined the association between hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with the risk of CRN. Methods: A cross-sectional study was performed on asymptomatic examinees who underwent a colonoscopy and serologic testing for hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCV Ab) between 2004 and 2015. Results: Of 155,674 participants who underwent serologic testing for HBsAg, 5476 (3.5%) were positive for HBsAg. The mean age of the study participants was 41.1 ± 9.1 years. The prevalence of CRN was higher in the HBsAg (+) than in HBsAg (-) participants (16.9% vs. 15.6%, p = 0.009). Even after adjusting for confounders, HBsAg positivity was correlated with an increased risk of CRN (odds ratio (OR), 1.10; 95% confidence interval (CI), 1.01–1.19; p = 0.025). Of 155,180 participants who underwent serologic testing for HCV Ab, only 240 (0.15%) were positive for HCV Ab. The prevalence of CRN was higher in HCV Ab (+) than in HCV Ab (-) participants (22.9% vs. 15.6%, p = 0.002). However, the association disappeared after adjusting for confounders (OR, 1.04; 95% CI, 0.72–1.50; p = 0.839). Conclusions: HBV infection was independently correlated with an increased risk of CRN. Our results indicate the possibility that HBV infection may contribute to colorectal carcinogenesis. Screening colonoscopy may have to be recommended more thoroughly for HBV-infected patients.
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Birkett N, Al-Zoughool M, Bird M, Baan RA, Zielinski J, Krewski D. Overview of biological mechanisms of human carcinogens. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2019; 22:288-359. [PMID: 31631808 DOI: 10.1080/10937404.2019.1643539] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
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Affiliation(s)
- Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mustafa Al-Zoughool
- Department of Community and Environmental Health, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Michael Bird
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Robert A Baan
- International Agency for Research on Cancer, Lyon, France
| | - Jan Zielinski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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Meng C, Liu T, Liu YW, Zhang LZ, Wang YL. Hepatitis B Virus cccDNA in Hepatocellular Carcinoma Tissue Increases the Risk of Recurrence After Liver Transplantation. Transplant Proc 2019; 51:3364-3368. [PMID: 31358449 DOI: 10.1016/j.transproceed.2019.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/23/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND High hepatitis B virus (HBV) DNA level is strongly associated with hepatocellular carcinoma (HCC) development in chronic HBV infection. The aim of this study was to investigate the association between intrahepatic HBV DNA titer and post-liver transplantation (LT) prognosis for HBV-related HCC (HBV-HCC) patients. METHODS A total of 60 patients with HBV-HCC who underwent LT were retrospectively studied. Using quantitative TaqMan fluorescent real-time polymerase chain reaction assay, HBV total DNA (tDNA) and covalently closed circular DNA (cccDNA) were both quantified in tumor tissue (TT) and adjacent non-tumor tissue (ANTT) from the explanted liver. RESULTS The loads of tDNA and cccDNA in ANTT were associated with serum HBV DNA levels. Multivariate analysis showed that the presence of vascular invasion and cccDNA in TT were independent risk factors for tumor recurrence. The group of patients with cccDNA titers ≥31ogl0 copies/μg in TT had significantly higher cumulative recurrence rates than those with <31ogl0 copies/μg group. The cccDNA titers predicted the tumor recurrence with an area under the receiver operating characteristic curve of 0.664. CONCLUSIONS Our findings would assist the clinical implementation of a more personalized therapy for tumor recurrence control and improve the prognosis of HBV-HCC patients.
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Affiliation(s)
- C Meng
- Department of Clinical Laboratory, Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - T Liu
- Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Y W Liu
- Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland
| | - L Z Zhang
- Department of Hepatobiliary Surgery, People's Hospital of Zhucheng City, Shandong, China
| | - Y L Wang
- Department of Clinical Laboratory, 2nd Hospital of Tianjin Medical University, Tianjin, China.
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Wei Z, Shen X, Ni B, Luo G, Tian Y, Sun Y. Contribution of hepatitis B virus X protein-induced aberrant microRNA expression to hepatocellular carcinoma pathogenesis. ACTA ACUST UNITED AC 2019; 43:113-123. [PMID: 31320813 PMCID: PMC6620039 DOI: 10.3906/biy-1807-196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hepatitis B virus-encoded X (HBX) protein plays important roles in Hepatocellular carcinoma (HCC). Previous studies have demonstrated that HBX can induce alterations in the expression of numerous microRNAs (miRNAs) involved in the carcinogenesis of various tumors. However, the global profile of liver miRNA changes induced by HBX has not been characterized. In this study, we conducted a miRNA microarray analysis to investigate the influence of HBX on the expression of total miRNAs in liver in relation to HCC. Comparative analysis of the data from human normal liver cells (L02) and human HCC cells (HepG2), with or without HBX, identified 19 differentially expressed miRNAs, including 5 with known association to HBX. Target gene prediction for the aberrantly expressed miRNAs identified a total of 304 potential target genes, involved in sundry pathways. Finally, pathway analysis of the HBXinduced miRNAs pathway showed that 5 of the total miRNAs formed an internetwork, suggesting that HBX might exert its pathological effects on hepatic cells through functional synergy with miRNAs that regulated common pathways in liver cells. Therefore, this work provides new insights into the mechanisms of HCC as well as potential diagnostic markers or therapeutic targets for use in clinical management of HCC.
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Affiliation(s)
- Zhiyuan Wei
- Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China.,Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
| | - Xiaohe Shen
- Department of Microbiology and Immunology, Shanxi Medical University , Taiyuan, Shanxi , P.R. China
| | - Bing Ni
- Department of Pathophysiology and High Altitude Pathology, Army Medical University (Third Military Medical University) , Chongqing , P.R. China.,Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China
| | - Gaoxing Luo
- Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
| | - Yi Tian
- Institute of Immunology, PLA, Army Medical University (Third Military Medical University) , Chongqing , P.R. China
| | - Yi Sun
- Southwest Hospital, Army Medical University (Third Military Medical University) , Chongqing , P. R. China
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Ding N, Maiuri AR, O'Hagan HM. The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2019; 780:69-81. [PMID: 31395351 PMCID: PMC6690501 DOI: 10.1016/j.mrrev.2017.09.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 09/25/2017] [Accepted: 09/27/2017] [Indexed: 12/15/2022]
Abstract
At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species (ROS), which can contribute to the initiation and development of many different human cancers. Aberrant epigenetic alterations that cause transcriptional silencing of tumor suppressor genes are also implicated in many diseases associated with inflammation, including cancer. However, it is not clear how altered epigenetic gene silencing is initiated during chronic inflammation. The high level of ROS at sites of inflammation is known to induce oxidative DNA damage in surrounding epithelial cells. Furthermore, DNA damage is known to trigger several responses, including recruitment of DNA repair proteins, transcriptional repression, chromatin modifications and other cell signaling events. Recruitment of epigenetic modifiers to chromatin in response to DNA damage results in transient covalent modifications to chromatin such as histone ubiquitination, acetylation and methylation and DNA methylation. DNA damage also alters non-coding RNA expression. All of these alterations have the potential to alter gene expression at sites of damage. Typically, these modifications and gene transcription are restored back to normal once the repair of the DNA damage is completed. However, chronic inflammation may induce sustained DNA damage and DNA damage responses that result in these transient covalent chromatin modifications becoming mitotically stable epigenetic alterations. Understanding how epigenetic alterations are initiated during chronic inflammation will allow us to develop pharmaceutical strategies to prevent or treat chronic inflammation-induced cancer. This review will focus on types of DNA damage and epigenetic alterations associated with chronic inflammatory diseases, the types of DNA damage and transient covalent chromatin modifications induced by inflammation and oxidative DNA damage and how these modifications may result in epigenetic alterations.
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Affiliation(s)
- Ning Ding
- Medical Sciences Program, School of Medicine, Indiana University, Bloomington, IN 47405, USA
| | - Ashley R Maiuri
- Medical Sciences Program, School of Medicine, Indiana University, Bloomington, IN 47405, USA
| | - Heather M O'Hagan
- Medical Sciences Program, School of Medicine, Indiana University, Bloomington, IN 47405, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
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Dhanasekaran R, Nault JC, Roberts LR, Zucman-Rossi J. Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Gastroenterology 2019; 156:492-509. [PMID: 30404026 PMCID: PMC6340723 DOI: 10.1053/j.gastro.2018.11.001] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 02/07/2023]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.
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Affiliation(s)
| | - Jean-Charles Nault
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jessica Zucman-Rossi
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Hôpital Europeen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
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Zhang C, Wang P, Li Y, Huang C, Ni W, Chen Y, Shi J, Chen G, Hu X, Ye M, Duan S, Wang K. Role of MicroRNAs in the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Anat Rec (Hoboken) 2018; 302:193-200. [PMID: 30312023 DOI: 10.1002/ar.23954] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 02/24/2018] [Accepted: 03/09/2018] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent liver malignancy that can be developed from nonalcoholic fatty liver disease (NAFLD). Numerous pathophysiological alterations, including insulin resistance, specific cytokine release, oxidative stress, and mitochondrial damage, are involved in the transition of NAFLD to cirrhosis and HCC. MicroRNAs, as post-transcriptional modulators, play a critical role in the pathogenesis of NAFLD-related HCC by regulating lipid metabolism, glucose homeostasis, cell proliferation, apoptosis, migration, and differentiation. This review summarizes the current progress of microRNAs in the risk and prognosis of NAFLD-related HCC. Anat Rec, 302:193-200, 2019. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Cheng Zhang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Ping Wang
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Yongqiang Li
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Changxin Huang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wei Ni
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yidan Chen
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Junping Shi
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Gongying Chen
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiangrong Hu
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Meng Ye
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Shiwei Duan
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Kaifeng Wang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
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