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Kim JS, Kim HS, Tak KY, Han JW, Nam H, Sung PS, Lee SW, Kwon JH, Bae SH, Choi JY, Yoon SK, Jang JW. Male preference for TERT alterations and HBV integration in young-age HBV-related HCC: implications for sex disparity. Clin Mol Hepatol 2025; 31:509-524. [PMID: 39743888 PMCID: PMC12016656 DOI: 10.3350/cmh.2024.0545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND/AIMS Hepatocellular carcinoma (HCC) exhibits significant sex disparities in incidence, yet its molecular mechanisms remain unclear. We explored the role of telomerase reverse transcriptase (TERT) genetic alterations and hepatitis B virus (HBV) integration, both known major contributors to HCC, in sex-specific risk for HBV-related HCC. METHODS We examined 310 HBV-related HCC tissues to investigate sex-specific TERT promoter (TERT-pro) mutations and HBV integration profiles, stratified by sex and age, and validated with single-cell RNA sequencing (scRNA-seq) data. RESULTS Tumors predominantly exhibited TERT-pro mutations (26.0% vs. 0%) and HBV-TERT integration (37.0% vs. 3.0%) compared to non-tumorous tissues. While TERT-pro mutations increased with age in both sexes, younger males (≤60 years) showed marked predominance compared to younger females. Males had significantly more HBV integrations at younger ages, while females initially had fewer integrations that gradually increased with age. Younger males' integrations showed significantly greater enrichment in the TERT locus compared to younger females, alongside a preference for promoters, PreS/S regions, and CpG islands. Overall, TERT genetic alterations were significantly sex-differential in younger individuals (75.3% in males vs. 23.1% in females) but not in older individuals (76.9% vs. 83.3%, respectively). These alterations were associated with increased TERT expression. The skewed TERT abnormalities in younger males were further corroborated by independent scRNA-seq data. CONCLUSION Our findings highlight the critical role of TERT alterations and HBV integration patterns in the male predominance of HCC incidence among younger HBV carriers, offering insights for future exploration to optimize sex-specific patient care and HCC surveillance strategies.
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Affiliation(s)
- Jin Seoub Kim
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Seon Kim
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kwon Yong Tak
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Won Han
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Heechul Nam
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung Won Lee
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung Hyun Kwon
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Chen Y, Dong Y, Wei S, Gao X, Li W, Zhao P. Genomic Integration of Hepatitis B Virus Into Human Hepatocytes in Early Childhood Cirrhosis. Liver Int 2025; 45:e70080. [PMID: 40130949 DOI: 10.1111/liv.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 02/09/2025] [Accepted: 03/17/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) remains a major global health problem. HBV DNA can be integrated into the human chromosomes. The integration in young cirrhotic chronic hepatitis B children has not been explored. This study aims to investigate HBV DNA integration in early childhood cirrhosis. METHODS Biopsy liver specimens from cirrhotic and matched non-cirrhotic chronic hepatitis B children were collected. HBV DNA integration was detected through targeted HBV DNA fragment capture sequencing. RESULTS Twenty cirrhotic and 20 non-cirrhotic children with chronic hepatitis B were included in the study. The cirrhotic group included 14 males and 6 females, and the non-cirrhotic group included 13 males and 7 females. Compared to non-cirrhotic children, cirrhotic children had lower serum HBsAg quantification (p = 0.001). The median number of HBV integrants in the cirrhotic group was 59 and that in the non-cirrhotic group was 98. No significant difference existed between the two groups (p = 0.529). In the multivariate linear regression analysis, serum HBV DNA level was correlated with the number of HBV integrants (p < 0.001, R2 = 0.322). Six differential intragenic high-frequency viral integration sites in cirrhotic children were revealed, all of which have protein-coding functions. CONCLUSION Several frequently integrated genes were observed in early childhood cirrhosis. Detailed associations between genetic alterations induced by HBV integration and early childhood cirrhosis need further exploration.
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Affiliation(s)
- Ying Chen
- Department of Clinical Laboratory, 962nd Hospital of PLA Joint Logistic Support Force, Harbin, Heilongjiang Province, China
| | - Yi Dong
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
| | - Shizhang Wei
- Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue Gao
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
| | - Weijie Li
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Pan Zhao
- The Fifth Medical Center (formerly Beijing 302 Hospital), Chinese PLA General Hospital, Beijing, China
- Xinxiang Medical University, Xinxiang, Henan Province, China
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Yang J, Zhou F, Luo X, Fang Y, Wang X, Liu X, Xiao R, Jiang D, Tang Y, Yang G, You L, Zhao Y. Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies. Cell Death Discov 2025; 11:84. [PMID: 40032852 DOI: 10.1038/s41420-025-02366-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 01/24/2025] [Accepted: 02/19/2025] [Indexed: 03/05/2025] Open
Abstract
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
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Affiliation(s)
- Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Feihan Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Xiyuan Luo
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Yuan Fang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Xing Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Xiaohong Liu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Ruiling Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Decheng Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Yuemeng Tang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, PR China.
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Li CL, Hsu CL, Lin YY, Ho MC, Hu RH, Tzeng ST, Wang YC, Tanaka Y, Chen PJ, Yeh SH. HBV DNA integration and somatic mutations in HCC patients with HBV-HCV dual infection reveals profiles intermediate between HBV- and HCV-related HCC. J Biomed Sci 2025; 32:2. [PMID: 39743539 PMCID: PMC11694426 DOI: 10.1186/s12929-024-01094-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/09/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND In regions with a high prevalence of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, coinfected patients face a heightened risk of developing hepatocellular carcinoma (HCC), termed HBV/HCV-related HCC (HBCV-HCC). We aimed to investigate the contribution of preexisting chronic hepatitis B (CHB) and subsequent chronic hepatitis C (CHC) to the development of HBCV-HCC. METHODS We examined HBV's involvement in 93 HBCV-HCC cases by analyzing HBV DNA integration as an indicator of HCC originating from HBV-infected hepatocytes, compared with 164 HBV-HCCs and 56 HCV-HCCs as controls. RESULTS Next generation sequencing revealed that 55% of HBCV-HCCs exhibited clonal HBV integration, which falls between the rates observed in HBV-HCCs (88%) and HCV-HCCs (7%), with similar integration patterns to HBV-HCCs. Common HCC somatic mutation analysis indicated HCV superinfection in HBCV-HCCs correlated with increased mutation rates in the telomerase reverse transcriptase (TERT) promoter and beta-catenin genes. Transcriptome analysis showed a prevalence of replicating HCV over HBV in HBCV-HCCs, with preexisting HBV exerting a proliferative role. The comparison of clinical characteristics revealed similarities between HBCV-HCC and HCV-HCC patients, including later onset for HBCV-HCC, possibly due to HCV superinfection slowing carcinogenesis. Notably, HBCV-HCCs with the same driver mutation, HBV integration at the TERT promoter, tended to develop later and showed a better prognosis post-tumor resection than HBV-HCCs. CONCLUSIONS Our findings shed light on the interplay between preexisting CHB and subsequent CHC in elevating the risk of HBCV-HCC. These insights are crucial for understanding viral etiology-specific carcinogenesis and guiding surveillance policies for HBCV-HCC post-antiviral therapy.
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Affiliation(s)
- Chiao-Ling Li
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Rey-Heng Hu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | | | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Center of Precision Medicine, National Taiwan University, Taipei, Taiwan.
| | - Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
- Center of Precision Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
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La Frazia S, Pauciullo S, Zulian V, Garbuglia AR. Viral Oncogenesis: Synergistic Role of Genome Integration and Persistence. Viruses 2024; 16:1965. [PMID: 39772271 PMCID: PMC11728759 DOI: 10.3390/v16121965] [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: 11/25/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
Persistence is a strategy used by many viruses to evade eradication by the immune system, ensuring their permanence and transmission within the host and optimizing viral fitness. During persistence, viruses can trigger various phenomena, including target organ damage, mainly due to an inflammatory state induced by infection, as well as cell proliferation and/or immortalization. In addition to immune evasion and chronic inflammation, factors contributing to viral persistence include low-level viral replication, the accumulation of viral mutants, and, most importantly, maintenance of the viral genome and reliance on viral oncoprotein production. This review focuses on the process of genome integration, which may occur at different stages of infection (e.g., HBV), during the chronic phase of infection (e.g., HPV, EBV), or as an essential part of the viral life cycle, as seen in retroviruses (HIV, HTLV-1). It also explores the close relationship between integration, persistence, and oncogenesis. Several models have been proposed to describe the genome integration process, including non-homologous recombination, looping, and microhomology models. Integration can occur either randomly or at specific genomic sites, often leading to genome destabilization. In some cases, integration results in the loss of genomic regions or impairs the regulation of oncogene and/or oncosuppressor expression, contributing to tumor development.
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Affiliation(s)
- Simone La Frazia
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
| | - Silvia Pauciullo
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
| | - Verdiana Zulian
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
| | - Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.); (A.R.G.)
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Liang H, Yang M, Luo D, Wu YK. Improving Adherence of Young Male Patients with HBV Infection to the Regular Follow-Up via Mobile Healthcare Platform Might Be Cost-Effective to Decrease the Morbidity of Advanced Liver Cancer. Patient Prefer Adherence 2024; 18:2581-2595. [PMID: 39717819 PMCID: PMC11665142 DOI: 10.2147/ppa.s497831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/13/2024] [Indexed: 12/25/2024] Open
Abstract
Background Young adults contribute substantially to the social economy. However, the number of young adults with liver cancer has increased recently. In addition, the mortality rate of these patients is high. Methods This retrospective study investigated the risk factors of young patients diagnosed with liver cancer over the past 12 years. Results The risk factors of liver cancer, including male, HBV infection, and family history of diseases, were more common in young patients. Nearly 80% of young patients (198/253) were tested as positive HBsAg. However, most of these patients did not visit doctors regularly, as recommended. Thus, 55.7% of young patients were diagnosed with advanced liver cancer. The aspartate aminotransferase (AST) levels were independently associated with advanced liver cancer (OR = 4.262, 95% CI = 1.559-11.65, P = 0.005) in the multivariable logistic regression. The 1-year survival rate of these patients was 19.4%. Conclusion The high-risk factors of liver cancer are common in young patients. The poor adherence to regularly visited doctors in young patients might contribute to the high ratio of advanced liver cancer. The 1-year survival rate of these patients is low. Improving patient's adherence via mobile healthcare platform and monitoring serum AST levels might decrease the incidence and mortality of liver cancer in young adults.
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Affiliation(s)
- Hao Liang
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan Province, People’s Republic of China
| | - Min Yang
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan Province, People’s Republic of China
| | - Dan Luo
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan Province, People’s Republic of China
| | - Ya-Kun Wu
- Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan Province, People’s Republic of China
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Zoulim F, Chen PJ, Dandri M, Kennedy PT, Seeger C. Hepatitis B virus DNA integration: Implications for diagnostics, therapy, and outcome. J Hepatol 2024; 81:1087-1099. [PMID: 38971531 DOI: 10.1016/j.jhep.2024.06.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/26/2024] [Accepted: 06/29/2024] [Indexed: 07/08/2024]
Abstract
Hepatitis B virus (HBV) DNA integration - originally recognised as a non-functional byproduct of the HBV life cycle - has now been accepted as a significant contributor to HBV pathogenesis and hepatitis D virus (HDV) persistence. Integrated HBV DNA is derived from linear genomic DNA present in viral particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of hepatitis B surface antigen (HBsAg) and HBx. DNA integration events accumulate over the course of viral infection, ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infections. HBV DNA integration events have primarily been investigated in the context of hepatocellular carcinoma development as they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and, presumably, induce epigenetic alterations, promoting tumour growth. More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response. Integrated DNA provides a source for envelope proteins required for HDV replication and hence represents a means for HDV persistence. Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection, which rely on HBsAg as a diagnostic marker. Integrated HBV DNA has been useful in assessing the turnover of infected hepatocytes which occurs during all phases of chronic hepatitis B including the initial phase of infection historically termed immune tolerant. HBV DNA integration has also been shown to impact the development of novel therapies targeting viral RNAs.
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Affiliation(s)
- Fabien Zoulim
- Université Claude Bernard Lyon 1, Hospices Civils de Lyon, INSERM, Lyon Hepatology Institute, Lyon, France.
| | - Pei-Jer Chen
- Hepatitis Research Center and Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Partner Site, Germany
| | - Patrick T Kennedy
- Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
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Ma Q, Li W, Wu W, Sun M. Exploring the active ingredients and mechanisms of Liujunzi decoction in treating hepatitis B: a study based on network pharmacology, molecular docking, and molecular dynamics simulations. Comput Methods Biomech Biomed Engin 2024:1-25. [PMID: 39534925 DOI: 10.1080/10255842.2024.2427117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/24/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Liujunzi decoction (LJZD) is commonly used to treat hepatitis B virus (HBV), though its active ingredients and mechanisms are not fully known. This study identified core targets and active components of LJZD for treating hepatitis B (HB) through network pharmacology, molecular docking, and molecular dynamics simulation. Screening from databases yielded 533 active components, 2619 targets for LJZD, and 2910 for HB, with 891 intersecting targets. STRING and CytoHubba analyses identified AR and VDR as core targets, with key pathways including PI3K-Akt and MAPK. The findings clarify LJZD's multicomponent, multitarget mechanisms, supporting its clinical application for HB treatment.
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Affiliation(s)
- Qing Ma
- Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenying Wu
- Department of Pharmacy, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Mei Sun
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Cheng CL, Lin YY, Hsu CL, Li CL, Yuan CT, Lai YY, Fang WQ, Chen PJ, Yeh SH, Tien HF. Unraveling the role of hepatitis B virus DNA integration in B-cell lymphomagenesis. Br J Cancer 2024; 131:996-1004. [PMID: 39026081 PMCID: PMC11405389 DOI: 10.1038/s41416-024-02763-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 06/08/2024] [Accepted: 06/12/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Studies have shown that hepatitis B virus (HBV)-associated B-cell non-Hodgkin lymphoma (NHL) constitutes a unique subgroup with distinct clinical features. It still leaves open the question of whether the integration of HBV DNA into the B-cell genome is a causal mechanism in the development of lymphoma. METHODS Using the hybridisation capture-based next generation sequencing and RNA sequencing, we characterised the HBV integration pattern in 45 HBV-associated B-cell NHL tumour tissues. RESULTS A total of 354 HBV integration sites were identified in 13 (28.9%) samples, indicating the relatively low integration frequency in B-cell NHLs. High plasma HBV DNA loads were not associated with the existence of HBV integration. The insertion sites distributed randomly across all the lymphoma genome without any preferential hotspot neither at the chromosomal level nor at the genetic level. Intriguingly, most HBV integrations were nonclonal in B-cell NHLs, implying that they did not confer a survival advantage. Analysis of the paired diagnosis-relapse samples showed the unstable status of HBV integrations during disease progression. Furthermore, transcriptomic analysis revealed the limited biological impact of HBV integration. CONCLUSION Our study provides an unbiased HBV integration map in B-cell NHLs, revealing the insignificant role of HBV DNA integration in B-cell lymphomagenesis.
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Affiliation(s)
- Chieh-Lung Cheng
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - You-Yu Lin
- Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan, ROC
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, ROC
| | - Chiao-Ling Li
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan, ROC
| | - Chang-Tsu Yuan
- Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan, ROC
| | - Ya-Yun Lai
- Microbial Genomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Wei-Quan Fang
- Division of New Drug, Center for Drug Evaluation, Taipei, Taiwan, ROC
| | - Pei-Jer Chen
- Microbial Genomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan, ROC
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
- Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.
| | - Hwei-Fang Tien
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC.
- Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan, ROC.
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Yang Z, Zeng J, Chen Y, Wang M, Luo H, Huang AL, Deng H, Hu Y. Detection of HBV DNA integration in plasma cell-free DNA of different HBV diseases utilizing DNA capture strategy. Virol Sin 2024; 39:655-666. [PMID: 38852920 PMCID: PMC11401475 DOI: 10.1016/j.virs.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/04/2024] [Indexed: 06/11/2024] Open
Abstract
The landscape of hepatitis B virus (HBV) integration in the plasma cell-free DNA (cfDNA) of HBV-infected patients with different stages of liver diseases [chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC)] remains unclear. In this study, we developed an improved strategy for detecting HBV DNA integration in plasma cfDNA, based on DNA probe capture and next-generation sequencing. Using this optimized strategy, we successfully detected HBV integration events in chimeric artificial DNA samples and HBV-infected HepG2-NTCP cells at day one post infection, with high sensitivity and accuracy. The characteristics of HBV integration events in the HBV-infected HepG2-NTCP cells and plasma cfDNA from HBV-infected individuals (CHB, LC, and HCC) were further investigated. A total of 112 and 333 integration breakpoints were detected in the HepG2-NTCP cells and 22 out of 25 (88%) clinical HBV-infected samples, respectively. In vivo analysis showed that the normalized number of support unique sequences (nnsus) in HCC was significantly higher than in CHB or LC patients (P values < 0.05). All integration breakpoints are randomly distributed on human chromosomes and are enriched in the HBV genome around nt 1800. The majority of integration breakpoints (61.86%) are located in the gene-coding region. Both non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ) interactions occurred during HBV integration across the three different stages of liver diseases. Our study provides evidence that HBV DNA integration can be detected in the plasma cfDNA of HBV-infected patients, including those with CHB, LC, or HCC, using this optimized strategy.
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Affiliation(s)
- Zerui Yang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Jingyan Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yueyue Chen
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Mengchun Wang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Hongchun Luo
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Haijun Deng
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Yuan Hu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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11
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Huang J, Ali T, Feldman DM, Theise ND. Androgen-Induced, β-Catenin-Activated Hepatocellular Adenomatosis with Spontaneous External Rupture. Diagnostics (Basel) 2024; 14:1473. [PMID: 39061609 PMCID: PMC11276095 DOI: 10.3390/diagnostics14141473] [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: 05/07/2024] [Revised: 05/29/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
Androgens have long been recognized as oncogenic agents. They can induce both benign and malignant hepatocellular neoplasms, including hepatocellular adenoma (HCA) and hepatocellular carcinoma, though the underlying mechanisms remain unclear. Androgen-induced liver tumors are most often solitary and clinically silent. Herein, we reported an androgen-induced HCA complicated by spontaneous rupture. The patient was a 24-year-old male presenting with fatigue, diminished libido, radiology-diagnosed hepatocellular adenomatosis for 3 years, and sudden-onset, severe, sharp, constant abdominal pain for one day. He used Aveed (testosterone undecanoate injection) from age 17 and completely stopped one year before his presentation. A physical exam showed touch pain and voluntary guarding in the right upper quadrant of the abdomen. An abdominal CT angiogram demonstrated multiple probable HCAs, with active hemorrhage of the largest one (6.6 × 6.2 × 5.1 cm) accompanied by large-volume hemoperitoneum. After being stabilized by a massive transfusion protocol and interventional embolization, he underwent a percutaneous liver core biopsy. The biopsy specimen displayed atypical hepatocytes forming dense cords and pseudoglands. The lesional cells diffusely stained β-catenin in nuclei and glutamine synthetase in cytoplasm. Compared to normal hepatocytes from control tissue, the tumor cells were positive for nuclear AR (androgen receptor) expression but had no increased EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) protein expression. The case indicated that androgen-induced hepatocellular neoplasms should be included in the differential diagnosis of acute abdomen.
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Affiliation(s)
- Jialing Huang
- Department of Pathology, Geisinger Medical Center, Geisinger Commonwealth School of Medicine, 100 N. Academy Ave, Danville, PA 17822, USA
| | - Towhid Ali
- Department of Radiology, Geisinger Medical Center, Geisinger Commonwealth School of Medicine, 100 N. Academy Ave, Danville, PA 17822, USA
| | - David M. Feldman
- Department of Gastroenterology and Hepatology, New York University Grossman School of Medicine, 550 1st Avenue, New York, NY 10016, USA
| | - Neil D. Theise
- Department of Pathology, NYU Langone Medical Center, New York University Grossman School of Medicine, 550 1st Avenue, New York, NY 10016, USA
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12
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Zhang S, Xiao X, Yi Y, Wang X, Zhu L, Shen Y, Lin D, Wu C. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal Transduct Target Ther 2024; 9:149. [PMID: 38890350 PMCID: PMC11189549 DOI: 10.1038/s41392-024-01848-7] [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: 01/01/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 06/20/2024] Open
Abstract
Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.
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Affiliation(s)
- Shaosen Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyi Xiao
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yonglin Yi
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyu Wang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Lingxuan Zhu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Changping Laboratory, 100021, Beijing, China
| | - Yanrong Shen
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- CAMS Oxford Institute, Chinese Academy of Medical Sciences, 100006, Beijing, China.
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13
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Zhang H, Ding J, Zhou Y. Quantitative PCR-based high-sensitivity detection of HBV-DNA levels reflects liver function deterioration in patients with hepatitis B virus-related cirrhosis. Am J Transl Res 2024; 16:2301-2309. [PMID: 39006275 PMCID: PMC11236653 DOI: 10.62347/bdlo2786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/20/2024] [Indexed: 07/16/2024]
Abstract
OBJECTIVES To investigate the clinical implication of quantitative polymerase chain reaction (PCR)-based high-sensitivity detection of hepatitis B virus (HBV)-DNA levels in patients with HBV-related liver cirrhosis (LC). METHODS From January 2020 to December 2022, 100 fasting serum samples were collected and retrospectively analyzed from patients with treated HBV-related LC attending the Suzhou Hospital of Integrated Traditional Chinese and Western Medicine and Suzhou Guangci Cancer Hospital. Patients were divided into a negative group (HBV-DNA < 20 IU/mL) and a positive group (HBV-DNA ≥ 20 IU/mL) according to their high-sensitivity HBV-DNA test results. The clinical characteristics and serological indicators of the two groups were compared, mainly including gender, age, liver function [total protein (TP), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL)], lipids [total cholesterol (TC) and triglycerides (TG)], platelets (PLT), five serum liver fibrosis markers [cholyglycine (CG), hyaluronic acid (HA), laminin (LN), precollagen type III (PCIII), and type IV collagen (IV-C)], serum gastrointestinal tumor markers [α-fetoprotein (AFP) and carcinoembryonic antigen (CEA)], and hepatitis B surface antigen (HBsAg). The differences between the two groups in terms of liver function Child-Pugh grades and the incidence of hepatocellular carcinoma (HCC) were also compared. RESULTS There were 39 patients in the positive group, including 29 males and 10 females, and 61 patients in the negative group, including 38 males and 23 females, with no statistically significant differences in gender and age distribution between the two groups (P > 0.05). The levels of serological indicators (TP, ALB, AST, GGT, ALP, TBIL, DBIL, IBIL, TC, TG, PLT, CG, HA, LN, PCIII, IV-C, AFP, CEA, and HBsAg) in both groups showed no significant differences (P > 0.05), but the ALT level in the positive group was higher than that in the negative group (P < 0.0001). The positive group had worse Child-Pugh grades and higher HCC incidence compared to the negative group (P < 0.0001, P = 0.028). CONCLUSIONS Patients with HBV-related LC and HBV-DNA ≥ 20 IU/mL have higher serum ALT levels, worse liver function Child-Pugh grades, and higher HCC incidence than those with HBV-DNA < 20 IU/mL. High-sensitivity HBV-DNA quantification can reflect the deterioration of liver function in patients with HBV-related LC to some extent.
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Affiliation(s)
- Hao Zhang
- Laboratory Department, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou 215000, Jiangsu, China
| | - Jiayun Ding
- Laboratory Department, Suzhou Guangci Cancer Hospital Suzhou 215000, Jiangsu, China
| | - Yingzhen Zhou
- Laboratory Department, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine Suzhou 215000, Jiangsu, China
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14
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Xiao H, Wei J, Yuan L, Li J, Zhang C, Liu G, Liu X. Sex hormones in COVID-19 severity: The quest for evidence and influence mechanisms. J Cell Mol Med 2024; 28:e18490. [PMID: 38923119 PMCID: PMC11194454 DOI: 10.1111/jcmm.18490] [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: 03/05/2024] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Studies have reported variable effects of sex hormones on serious diseases. Severe disease and mortality rates in COVID-19 show marked gender differences that may be related to sex hormones. Sex hormones regulate the expression of the viral receptors ACE2 and TMPRSS2, which affect the extent of viral infection and consequently cause variable outcomes. In addition, sex hormones have complex regulatory mechanisms that affect the immune response to viruses. These hormones also affect metabolism, leading to visceral obesity and severe disease can result from complications such as thrombosis. This review presents the latest researches on the regulatory functions of hormones in viral receptors, immune responses, complications as well as their role in COVID-19 progression. It also discusses the therapeutic possibilities of these hormones by reviewing the recent findings of clinical and assay studies.
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Affiliation(s)
- Haiqing Xiao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Jiayi Wei
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Lunzhi Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Jiayuan Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Chang Zhang
- Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen)Fudan UniversityXiamenChina
| | - Gang Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, Institute of Artificial Intelligence, School of Public HealthXiamen UniversityXiamenChina
| | - Xuan Liu
- Clinical Center for Biotherapy, Zhongshan Hospital (Xiamen)Fudan UniversityXiamenChina
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15
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Qiao L, Li C, Lin W, He X, Mi J, Tong Y, Gao J. ViroISDC: a method for calling integration sites of hepatitis B virus based on feature encoding. BMC Bioinformatics 2024; 25:177. [PMID: 38704528 PMCID: PMC11070082 DOI: 10.1186/s12859-024-05763-0] [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: 09/22/2023] [Accepted: 03/26/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) integrates into human chromosomes and can lead to genomic instability and hepatocarcinogenesis. Current tools for HBV integration site detection lack accuracy and stability. RESULTS This study proposes a deep learning-based method, named ViroISDC, for detecting integration sites. ViroISDC generates corresponding grammar rules and encodes the characteristics of the language data to predict integration sites accurately. Compared with Lumpy, Pindel, Seeksv, and SurVirus, ViroISDC exhibits better overall performance and is less sensitive to sequencing depth and integration sequence length, displaying good reliability, stability, and generality. Further downstream analysis of integrated sites detected by ViroISDC reveals the integration patterns and features of HBV. It is observed that HBV integration exhibits specific chromosomal preferences and tends to integrate into cancerous tissue. Moreover, HBV integration frequency was higher in males than females, and high-frequency integration sites were more likely to be present on hepatocarcinogenesis- and anti-cancer-related genes, validating the reliability of the ViroISDC. CONCLUSIONS ViroISDC pipeline exhibits superior precision, stability, and reliability across various datasets when compared to similar software. It is invaluable in exploring HBV infection in the human body, holding significant implications for the diagnosis, treatment, and prognosis assessment of HCC.
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Affiliation(s)
- Lei Qiao
- College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Chang Li
- College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Wei Lin
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Xiaoqi He
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Jia Mi
- College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yigang Tong
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Jingyang Gao
- College of Information Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
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16
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Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
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Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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17
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Funato K, Miyake N, Sekiba K, Miyakawa Y, Seimiya T, Shibata C, Kishikawa T, Otsuka M. Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA. Hepatol Commun 2023; 7:e0313. [PMID: 37938099 PMCID: PMC10635605 DOI: 10.1097/hc9.0000000000000313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/18/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.
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Affiliation(s)
- Kazuyoshi Funato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nozomi Miyake
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
| | - Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yu Miyakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chikako Shibata
- 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
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
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18
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Choi S, Kim BK, Yon DK, Lee SW, Lee HG, Chang HH, Park S, Koyanagi A, Jacob L, Dragioti E, Radua J, Shin JI, Kim SU, Smith L. Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990-2019: A DALY-based analysis of the Global Burden of Disease 2019 study. Clin Mol Hepatol 2023; 29:433-452. [PMID: 36597018 PMCID: PMC10121317 DOI: 10.3350/cmh.2022.0316] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/16/2022] [Accepted: 12/27/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS Global distribution of dominant liver cancer aetiologies has significantly changed over the past decades. This study analyzed the updated temporal trends of liver cancer aetiologies and sociodemographic status in 204 countries and territories from 1990 to 2019. METHODS The Global Burden of Disease 2019 report was used for statistical analysis. In addition, we performed stratification analysis to five quintiles using sociodemographic index and 21 geographic regions. RESULTS The crude numbers of liver cancer disease-adjusted life years (DALYs) and deaths significantly increased during the study period (DALYs; 11,278,630 in 1990 and 12,528,422 in 2019, deaths; 365,215 in 1990 and 484,577 in 2019). However, the Age-standardized DALY and mortality rates decreased. Hepatitis B virus (HBV) remains the leading cause of liver cancer DALYs and mortality, followed by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). Although Age-standardized DALY and mortality rates of liver cancer due to HBV and HCV have decreased, the rates due to alcohol consumption and NASH/NAFLD have increased. In 2019, the population of the East Asia region had the highest Age-standardized DALY and mortality rates, followed by high-income Asia-Pacific and Central Asia populations. Although East Asia and high-income Asia-Pacific regions showed a decrease during the study period, Age-standardized DALY rates increased in Central Asia. High-income North American and Australasian populations also showed a significant increase in Age-standardized DALY. CONCLUSION Liver cancer remains an ongoing global threat. The burden of liver cancer associated with alcohol consumption and NASH/NAFLD is markedly increasing and projected to continuously increase.
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Affiliation(s)
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Dong Keon Yon
- Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Korea
| | - Seung Won Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea
| | | | | | - Seoyeon Park
- Yonsei University College of Medicine, Seoul, Korea
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, Dr. Antoni Pujadas, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies, Pg. Lluis Companys 23, Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, Dr. Antoni Pujadas, Barcelona, Spain
- Department of Physical Medicine and Rehabilitation, Lariboisière-Fernand Widal Hospital, AP-HP, University Paris Cité, Paris, France
| | - Elena Dragioti
- Pain and Rehabilitation Centre, and Department of Health, Medicine and Caring Sciences, Linkoping University, Linkoping, Sweden
| | - Joaquim Radua
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain
- Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Lee Smith
- Centre for Health, Performance, and Wellbeing, Anglia Ruskin University, Cambridge, UK
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19
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Zhang L, Wu J, Wu Q, Zhang X, Lin S, Ran W, Zhu L, Tang C, Wang X. Sex steroid axes in determining male predominance in hepatocellular carcinoma. Cancer Lett 2023; 555:216037. [PMID: 36563929 DOI: 10.1016/j.canlet.2022.216037] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. The mechanisms for male propensity in HCC incidence, prognosis and treatment responses are complicated and remain inconclusive. Sex-biased molecular signatures in carcinogenesis, viral infections and immune responses have been studied predominantly within the context of sex hormones effects. This review integrates current knowledge on the mechanisms through which the hormones regulate HCC development in sexually dimorphic fashion. Firstly, the androgen/androgen receptor (AR) accelerate cell proliferation and virus infection, especially during the initial stage of HCC, while estrogen/estrogen receptor (ER) function in an opposite way to induce cell apoptosis and immune responses. Interestingly, the controversial effects of AR in late stage of HCC metastasis are summarized and the reasons are attributed to inconsistent cancer grading or experimental models between the studies. In addition, the new insights into these intricate cellular and molecular mechanisms underlying sexual dimorphism are fully discussed. A detailed understanding of sex hormones-associated regulation to male predominance in HCC may help to develop personalized therapeutic strategies in high-risk populations.
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Affiliation(s)
- Lei Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - JinFeng Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - QiuMei Wu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - XiangJuan Zhang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ShuaiCai Lin
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - WanLi Ran
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Li Zhu
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - ChengYan Tang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Xing Wang
- Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
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20
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Xie J, Ding Y, Li X, Pu R, Liu W, Li P, Yin J. Association of ESR1 gene polymorphisms with the susceptibility to Hepatitis B virus infection and the clinical outcomes. J Med Virol 2023; 95:e28510. [PMID: 36661054 DOI: 10.1002/jmv.28510] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/30/2022] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
Estrogen receptor alpha (ESR1) has been implicated in the pathological process of Hepatitis B virus (HBV) infection and is probably an important determinant for gender differences. In this study, a total of 975 subjects including 368 healthy controls, 323 hepatocellular carcinoma (HCC) patients with HBsAg positive, and 284 HBV-infected subjects without HCC were included. Three single nucleotide polymorphisms of ESR1 (rs2234693, rs2077647, rs2228480) were detected to investigate the correlation between ESR1 polymorphisms and the susceptibility to HBV persistence and the clinical outcomes. The association of ESR1 polymorphisms with HCC prognosis was investigated in our cohort enrolling 376 HBV-HCC patients. The frequency of rs2234693 C allele was lower in chronic Hepatitis B (CHB) and liver cirrhosis (LC) than that in HCC patients in the males (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.41-0.96). rs2228480 A allele was associated with increased risk of LC (AOR = 2.20, 95% CI = 1.06-4.56) in HBV genotype C, and significantly decreased the risk of HCC recurrence (p = 0.010) and ESR1 mRNA level in tumor tissues (p = 0.032). Haplotype C-G-G was associated with significantly increased risk of HBV persistence (OR = 1.37, 95% CI = 1.08-1.73), while it was opposite for C-A-G and T-G-G (OR = 0.41, 95% CI = 0.27-0.62; OR = 0.53, 95% CI = 0.32-0.85, respectively). These results imply that combinations of these ESR1 polymorphisms may be valuable for the prediction of HBV persistence.
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Affiliation(s)
- Jiaxin Xie
- Department of High Altitude Operational Medicine, Army Medical University, Chongqing, China
| | - Yibo Ding
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Xiaopan Li
- Department of Health Management Center, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China
| | - Rui Pu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Wenbin Liu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Peng Li
- Department of High Altitude Operational Medicine, Army Medical University, Chongqing, China
| | - Jianhua Yin
- Department of Epidemiology, Naval Medical University, Shanghai, China
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21
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Yeh SH, Li CL, Lin YY, Ho MC, Wang YC, Tseng ST, Chen PJ. Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC. Cell Mol Gastroenterol Hepatol 2023; 15:921-929. [PMID: 36690297 PMCID: PMC9972564 DOI: 10.1016/j.jcmgh.2023.01.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/24/2022] [Accepted: 01/02/2023] [Indexed: 01/25/2023]
Abstract
Hepatitis B virus (HBV) DNA integration is an incidental event in the virus replication cycle and occurs in less than 1% of infected hepatocytes during viral infection. However, HBV DNA is present in the genome of approximately 90% of HBV-related HCCs and is the most common somatic mutation. Whole genome sequencing of liver tissues from chronic hepatitis B patients showed integration occurring at random positions in human chromosomes; however, in the genomes of HBV-related HCC patients, there are integration hotspots. Both the enrichment of the HBV-integration proportion in HCC and the emergence of integration hotspots suggested a strong positive selection of HBV-integrated hepatocytes to progress to HCC. The activation of HBV integration hotspot genes, such as telomerase (TERT) or histone methyltransferase (MLL4/KMT2B), resembles insertional mutagenesis by oncogenic animal retroviruses. These candidate oncogenic genes might shed new light on HBV-related HCC biology and become targets for new cancer therapies. Finally, the HBV integrations in individual HCC contain unique sequences at the junctions, such as virus-host chimera DNA (vh-DNA) presumably being a signature molecule for individual HCC. HBV integration may thus provide a new cell-free tumor DNA biomarker to monitor residual HCC after curative therapies or to track the development of de novo HCC.
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Affiliation(s)
- Shiou-Hwei Yeh
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan; National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
| | - Chiao-Ling Li
- Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University College of Life Science, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | | | | | - Pei-Jer Chen
- National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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22
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Wang SH, Yeh SH, Chen PJ. Androgen Enhances Aflatoxin-induced Genotoxicity and Inflammation to Liver Cancer in Male Hepatitis B Patients. Cell Mol Gastroenterol Hepatol 2022; 15:507-508. [PMID: 36427539 PMCID: PMC9880974 DOI: 10.1016/j.jcmgh.2022.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 10/28/2022] [Accepted: 11/03/2022] [Indexed: 11/24/2022]
Affiliation(s)
| | - Shiou-Hwei Yeh
- NTU Centers of Genomic and Precision Medicine, Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Hepatitis Research Center, National Taiwan University Hospital, NTU Centers of Genomic and Precision Medicine, College of Medicine, National Taiwan University, Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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23
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Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Borkowski V, Segal M, Mukhtar M, Mohammed M, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, Mumtaz K. Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data. World J Gastrointest Oncol 2022; 14:1856-1873. [PMID: 36187396 PMCID: PMC9516659 DOI: 10.4251/wjgo.v14.i9.1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/26/2022] [Accepted: 08/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.
AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.
METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.
RESULTS Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.
CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Eli Cohen
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Naima Hashi
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Sharjeel Syed
- Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
| | - Emmanuel Boateng
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Mary Nemer
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
| | - Dexter Hadley
- Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Sajid Jalil
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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24
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Zhao Y, Jia Y, Qi S, Wu C, Wu J, Zhang R, Li J, Guo Z. Comparison of Postoperative Prognosis Among HBV-Related, HCV-Related, and Non-HBV Non-HCV Hepatocellular Carcinomas: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2022; 22. [DOI: 10.5812/hepatmon-121820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 01/03/2025]
Abstract
Context: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and different hepatitis viruses might affect the prognosis of patients with HCC. Objectives: This study aimed to reveal the differences in the postoperative prognosis of patients with hepatitis B virus-related HCC (HBV-HCC), hepatitis C virus-related HCC (HCV-HCC), and non-HBV non-HCV hepatocellular carcinoma (NBNC-HCC). Methods: The databases PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for articles published until April 2022. Stata software version 12 and Review Manager version 5.4 were used to conduct the meta-analysis, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was adopted in this study. Results: In the present study, 26 papers on a total of 20381 participants who met the inclusion criteria were analyzed. The 5-year overall survival in the HBV-HCC and HCV-HCC groups was lower than in the NBNC-HCC group (HBV-HCC vs. NBNC-HCC, P = 0.005; HCV-HCC vs. NBNC-HCC, P = 0.001). Patients with HBV-HCC and HCV-HCC had worse 5-year recurrence-free survival than patients with NBNC-HCC (HBV-HCC vs. NBNC-HCC, P = 0; HCV-HCC vs. NBNC-HCC, P = 0). In addition, the 5-year recurrence-free rate in the HCV-HCC group was lower than in the HBV-HCC group (P = 0). The observed association between serum alpha-fetoprotein levels and the postoperative prognosis was inconsistent in different subgroups. Conclusions: Patients with NBNC-HCC had a significantly better postoperative prognosis than those with virus-related HCC. The alpha-fetoprotein levels significantly correlated with the postoperative prognosis of patients with HCC.
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25
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Li Y, Li R, Cheng D, Fu X, Fu L, Peng S. The potential of CircRNA1002 as a biomarker in hepatitis B virus-related hepatocellular carcinoma. PeerJ 2022; 10:e13640. [PMID: 35782101 PMCID: PMC9248787 DOI: 10.7717/peerj.13640] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 06/06/2022] [Indexed: 01/17/2023] Open
Abstract
Background Although hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, there is a lack of effective diagnostic measures. Circular RNAs (circRNAs) can be used as biomarkers for monitoring the occurrence and development of HCC. However, a convenient and reliable serum circRNA biomarker is not currently available. Materials & Methods CircRNA expression profiles were explored using high-throughput sequencing technology, and targeted circRNAs and mRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). The biological functions of circRNAs were investigated using Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Downstream miRNAs and mRNAs of dysregulated circRNAs were predicted using TargetScan, miRanda, and miRDB; then circRNA-miRNA-mRNA interaction networks were constructed based on sequencing data and the Cancer Genome Atlas (TCGA). Results A total of 50,327 circRNAs were identified, with 1,187 circRNAs significantly differentially expressed between hepatitis B virus (HBV)-related HCC and HBV asymptomatic carriers. Among these circRNAs, four (circRNA1002, circRNA7941, circRNA 39338, and circRNA44142) were validated by RT-qPCR as being statistically different either in HCC tissue or serum samples. circRNA1002 was significantly down-regulated in both HCC serum and tissue, indicating its reliability. Bioinformatics analysis showed that circRNA1002-associated genes were enriched in GO terms relating to hormone pathway and cell-cell interaction processes, which are involved in the progression of HCC. Conclusion Our circRNA analysis of HCC patients and HBV asymptomatic carriers showed that circRNA1002 may be a reliable serum biomarker for HCC. These results could provide an improved assay for the early detection of HCC.
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Affiliation(s)
- Ying Li
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Ronghua Li
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Da Cheng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Xiaoyu Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
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26
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Péneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro J, Paradis V, Blanc JF, Letouzé E, Nault JC, Amaddeo G, Zucman-Rossi J. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut 2022; 71:616-626. [PMID: 33563643 PMCID: PMC8862055 DOI: 10.1136/gutjnl-2020-323153] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features. DESIGN A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping. RESULTS Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis. CONCLUSION Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.
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Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Sandrine Imbeaud
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Tiziana La Bella
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Theo Z Hirsch
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Julien Calderaro
- Service d’Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - Valerie Paradis
- Service de Pathologie, Hôpital Beaujon, APHP, Clichy, France,Université Paris Diderot, CNRS, Centre de Recherche 27 sur l'Inflammation (CRI), Paris, France
| | - Jean-Frederic Blanc
- Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France,Service de Pathologie, CHU Bordeaux GH Pellegrin, Bordeaux, France,Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, Bordeaux, France
| | - Eric Letouzé
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France,Service d’Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Bobigny, France
| | - Giuliana Amaddeo
- Service d’Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de recherche biomedicale, Creteil, Île-de-France, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France .,Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France.,Hôpital Européen Georges Pompidou, AP-HP, Paris, France
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27
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Chen C, Chang H. Time trend and age‐specific gender difference in the incidence of liver cancer from 2009 to 2018 in Taiwan. ADVANCES IN DIGESTIVE MEDICINE 2022. [DOI: 10.1002/aid2.13313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Chuen‐Fei Chen
- Department of Medicine Mackay Medical College New Taipei City Taiwan
| | - Hung‐Chuen Chang
- Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho‐Su Memorial Hospital Taipei Taiwan
- School of Medicine Fu Jen Catholic University New Taipei City Taiwan
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28
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Bousali M, Karamitros T. Hepatitis B Virus Integration into Transcriptionally Active Loci and HBV-Associated Hepatocellular Carcinoma. Microorganisms 2022; 10:microorganisms10020253. [PMID: 35208708 PMCID: PMC8879149 DOI: 10.3390/microorganisms10020253] [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: 12/31/2021] [Revised: 01/10/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatitis B Virus (HBV) DNA integrations into the human genome are considered major causative factors to HBV-associated hepatocellular carcinoma development. In the present study, we investigated whether HBV preferentially integrates parts of its genome in specific genes and evaluated the contribution of the integrations in HCC development per gene. We applied dedicated in-house developed pipelines on all of the available HBV DNA integration data and performed a statistical analysis to identify genes that could be characterized as hotspots of integrations, along with the evaluation of their association with HBV-HCC. Our results suggest that 15 genes are recurrently affected by HBV integrations and they are significantly associated with HBV-HCC. Further studies that focus on HBV integrations disrupting these genes are mandatory in order to understand the role of HBV integrations in clonal advantage gain and oncogenesis promotion, as well as to determine whether inhibition of the HBV-disrupted genes can provide a therapy strategy for HBV-HCC.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Correspondence: ; Tel.: +30-210-6478871
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [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: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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Gerlich W. Hepatitis B virus - an anaerobic organism? J Hepatol 2021; 75:16-18. [PMID: 33820670 DOI: 10.1016/j.jhep.2021.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Wolfram Gerlich
- Institute for Medical Virology, Justus Liebig University Giessen, Germany.
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Wang Y, Wang M, Li H, Chen K, Zeng H, Bi X, Zhu Z, Jiao Y, Wang Y, Zhu J, Zhao H, Liu X, Dai C, Fan C, Zhao C, Guo D, Zhao H, Zhou J, Wang D, Wu Z, Zhao X, Cui W, Zhang X, Cai J, Chen W, Qu C. A male-ABCD algorithm for hepatocellular carcinoma risk prediction in HBsAg carriers. Chin J Cancer Res 2021; 33:352-363. [PMID: 34321832 PMCID: PMC8286891 DOI: 10.21147/j.issn.1000-9604.2021.03.07] [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: 02/18/2021] [Accepted: 04/28/2021] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults. METHODS HBsAg-positive males of 35-69 years old (N=6,153) were included from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction. RESULTS With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT (γ-glutamyl-transpeptidase), counts of platelets, white cells, concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91 (0.90-0.93), larger than existing models. At 1.5 points of risk score, 26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk, with positive prediction value of 22.85% and 12.35%, respectively. CONCLUSIONS Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.
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Affiliation(s)
- Yuting Wang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Minjie Wang
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - He Li
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Kun Chen
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hongmei Zeng
- National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Zhu
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuchen Jiao
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong Wang
- Department of Ultrasonography, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jian Zhu
- Qidong Liver Cancer Institute & Qidong People’s Hospital, Qidong 226200, China
| | - Hui Zhao
- Lingbi Center for Disease Control and Prevention, Suzhou 234200, China
| | - Xiang Liu
- Mengcheng Center for Disease Control and Prevention, Bozhou 233500, China
| | - Chunyun Dai
- Sheyang Center for Disease Control and Prevention, Yancheng 224300, China
| | - Chunsun Fan
- Qidong Liver Cancer Institute & Qidong People’s Hospital, Qidong 226200, China
| | - Can Zhao
- Shenqiu County Center for Disease Control and Prevention, Zhoukou 411624, China
| | - Deyin Guo
- Dancheng Center for Disease Control and Prevention, Zhoukou 477150, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dongmei Wang
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhiyuan Wu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinming Zhao
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei Cui
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Nutrition, T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wanqing Chen
- Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chunfeng Qu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Lin SY, Zhang A, Lian J, Wang J, Chang TT, Lin YJ, Song W, Su YH. Recurrent HBV Integration Targets as Potential Drivers in Hepatocellular Carcinoma. Cells 2021; 10:cells10061294. [PMID: 34071075 PMCID: PMC8224658 DOI: 10.3390/cells10061294] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC), frequently with HBV integrating into the host genome. HBV integration, found in 85% of HBV-associated HCC (HBV–HCC) tissue samples, has been suggested to be oncogenic. Here, we investigated the potential of HBV–HCC driver identification via the characterization of recurrently targeted genes (RTGs). A total of 18,596 HBV integration sites from our in-house study and others were analyzed. RTGs were identified by applying three criteria: at least two HCC subjects, reported by at least two studies, and the number of reporting studies. A total of 396 RTGs were identified. Among the 28 most frequent RTGs, defined as affected in at least 10 HCC patients, 23 (82%) were associated with carcinogenesis and 5 (18%) had no known function. Available breakpoint positions from the three most frequent RTGs, TERT, MLL4/KMT2B, and PLEKHG4B, were analyzed. Mutual exclusivity of TERT promoter mutation and HBV integration into TERT was observed. We present an RTG consensus through comprehensive analysis to enable the potential identification and discovery of HCC drivers for drug development and disease management.
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Affiliation(s)
- Selena Y. Lin
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Adam Zhang
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
| | - Jessica Lian
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
| | - Jeremy Wang
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Medical College, Tainan 704, Taiwan;
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Medical College, Tainan 704, Taiwan;
| | - Wei Song
- JBS Science, Inc., Doylestown, PA 18902, USA; (S.Y.L.); (J.W.); (W.S.)
| | - Ying-Hsiu Su
- The Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; (A.Z.); (J.L.)
- Correspondence: ; Tel.: +215-489-4907
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Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance. Cancers (Basel) 2021; 13:cancers13102454. [PMID: 34070067 PMCID: PMC8158142 DOI: 10.3390/cancers13102454] [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: 03/31/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatitis B virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC). Understanding the unique features for HBV-induced HCC can shed new light on the unmet needs in its early diagnosis and effective therapy. During decades of chronic hepatitis B, hepatocytes undergoing repeated damage and regeneration accumulate genetic changes predisposing to HCC development. In addition to traditional mutations in viral and cellular oncogenes, HBV integration into the cell chromosomes is an alternative genetic change contributing to hepatocarcinogenesis. A striking male dominance in HBV-related HCC further highlights an interaction between androgen sex hormone and viral factors, which contributes to the gender difference via stimulating viral replication and activation of oncogenes preferentially in male patients. Meanwhile, a novel circulating tumor biomarker generated by HBV integration shows great potential for the early diagnosis of HCC. These unique HBV-induced hepatocarcinogenic mechanisms provide new insights for the future development of superior diagnosis and treatment strategies. Abstract Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.
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Péneau C, Zucman-Rossi J, Nault JC. Genomics of Viral Hepatitis-Associated Liver Tumors. J Clin Med 2021; 10:1827. [PMID: 33922394 PMCID: PMC8122827 DOI: 10.3390/jcm10091827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 12/25/2022] Open
Abstract
Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
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Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, F-93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, F-93000 Bobigny, France
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Garcia-Garcia S, Cortese MF, Rodríguez-Algarra F, Tabernero D, Rando-Segura A, Quer J, Buti M, Rodríguez-Frías F. Next-generation sequencing for the diagnosis of hepatitis B: current status and future prospects. Expert Rev Mol Diagn 2021; 21:381-396. [PMID: 33880971 DOI: 10.1080/14737159.2021.1913055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis B virus (HBV) causes a complex and persistent infection with a major impact on patients health. Viral-genome sequencing can provide valuable information for characterizing virus genotype, infection dynamics and drug and vaccine resistance. AREAS COVERED This article reviews the current literature to describe the next-generation sequencing progress that facilitated a more comprehensive study of HBV quasispecies in diagnosis and clinical monitoring. EXPERT OPINION HBV variability plays a key role in liver disease progression and treatment efficacy. Second-generation sequencing improved the sensitivity for detecting and quantifying mutations, mixed genotypes and viral recombination. Third-generation sequencing enables the analysis of the entire HBV genome, although the high error rate limits its use in clinical practice.
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Affiliation(s)
- Selene Garcia-Garcia
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco Rodríguez-Algarra
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David Tabernero
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
| | - Ariadna Rando-Segura
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Josep Quer
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Maria Buti
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Francisco Rodríguez-Frías
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
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Inhibition of androgen/AR signaling inhibits diethylnitrosamine (DEN) induced tumour initiation and remodels liver immune cell networks. Sci Rep 2021; 11:3646. [PMID: 33574348 PMCID: PMC7878907 DOI: 10.1038/s41598-021-82252-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 01/11/2021] [Indexed: 12/13/2022] Open
Abstract
A promotional role for androgen receptor (AR) signaling in hepatocellular carcinogenesis is emerging. In pre-clinical models, including diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC), anti-androgen therapies delay hepatocarcinogenesis. However, pharmacologic anti-androgen therapy in advanced HCC patients fails, suggesting that AR plays a role in HCC onset. This study aims to characterize AR expression and function throughout DEN-induced liver inflammation and carcinogenesis and evaluate the efficacy of prophylactic AR antagonism to prevent hepatocarcinogenesis. We demonstrate that pharmacologic AR antagonism with enzalutamide inhibits hepatocellular carcinogenesis. With enzalutamide treatment, we observe decreased CYP2E1 expression, reducing DEN-induced hepatocyte death and DNA ethyl-adducts. AR protein expression analyses show that DEN causes an initial upregulation of AR in portal fibroblasts and leukocytes, but not hepatocytes, suggesting that hepatocyte-autonomous AR signaling is not essential for DEN-induced carcinogenesis. Ablating androgen signaling by surgical castration reduced pre-carcinogen Kupffer cell populations but did not alter DEN-mediated immune cell recruitment nor AR expression. In this study, we identified that anti-androgen interventions modulate mutagenic DNA adducts, tumour initiation, and immune cell composition. Additionally, we find that AR expression in hepatocytes is not present during nor required for early DEN-mediated carcinogenesis.
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Salimi-Jeda A, Badrzadeh F, Esghaei M, Abdoli A. The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches. Cancer Treat Res Commun 2021; 27:100323. [PMID: 33530025 DOI: 10.1016/j.ctarc.2021.100323] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/21/2022]
Abstract
Human telomerase reverse transcriptase (hTERT) is an enzyme that is critically involved in elongating and maintaining telomeres length to control cell life span and replicative potential. Telomerase activity is continuously expressed in human germ-line cells and most cancer cells, whereas it is suppressed in most somatic cells. In normal cells, by reducing telomerase activity and progressively shortening the telomeres, the cells progress to the senescence or apoptosis process. However, in cancer cells, telomere lengths remain constant due to telomerase's reactivation, and cells continue to proliferate and inhibit apoptosis, and ultimately lead to cancer development and human death due to metastasis. Studies demonstrated that several DNA and RNA oncoviruses could interact with telomerase by integrating their genome sequence within the host cell telomeres specifically. Through the activation of the hTERT promoter and lengthening the telomere, these cells contributes to cancer development. Since oncoviruses can activate telomerase and increase hTERT expression, there are several therapeutic strategies based on targeting the telomerase of cancer cells like telomerase-targeted peptide vaccines, hTERT-targeting dendritic cells (DCs), hTERT-targeting gene therapy, and hTERT-targeting CRISPR/Cas9 system that can overcome tumor-mediated toleration mechanisms and specifically apoptosis in cancer cells. This study reviews available data on the molecular structure of telomerase and the role of oncoviruses and telomerase interaction in cancer development and telomerase-dependent therapeutic approaches to conquest the cancer cells.
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Affiliation(s)
- Ali Salimi-Jeda
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Fariba Badrzadeh
- Faculti of Medicine, Golestan University of Medical sciences, Golestan, Iran.
| | - Maryam Esghaei
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Asghar Abdoli
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.
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Li M, Du M, Cong H, Gu Y, Fang Y, Li J, Gan Y, Tu H, Gu J, Xia Q. Characterization of hepatitis B virus DNA integration patterns in intrahepatic cholangiocarcinoma. Hepatol Res 2021; 51:102-115. [PMID: 33037855 DOI: 10.1111/hepr.13580] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/19/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022]
Abstract
AIM Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV-related ICC. METHODS The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high-throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. RESULTS Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high-throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV-DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV-DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para-ICC tissues. CONCLUSIONS Taken together, HBV integration is a common event in HBV-related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC.
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Affiliation(s)
- Mengge Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Du
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Cong
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyuan Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Emergency, Nanjing First Hospital, Nanjing, China
| | - Yuan Fang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jin Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Gan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Tu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinyang Gu
- Department of Transplantation, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Li CL, Ho MC, Lin YY, Tzeng ST, Chen YJ, Pai HY, Wang YC, Chen CL, Lee YH, Chen DS, Yeh SH, Chen PJ. Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer. Hepatology 2020; 72:2063-2076. [PMID: 32171027 DOI: 10.1002/hep.31230] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/21/2020] [Accepted: 02/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. APPROACH AND RESULTS HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. CONCLUSIONS vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.
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Affiliation(s)
- Chiao-Ling Li
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Yun-Ju Chen
- TCM Biotech International Corp., Taipei, Taiwan
| | | | | | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Hsin Lee
- Department of Surgery, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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40
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Harding JJ, Kelley RK, Tan B, Capanu M, Do GK, Shia J, Chou JF, Ferrer CS, Boussayoud C, Muenkel K, Yarmohammadi H, El Dika I, Khalil DN, Ruiz C, Rodriguez‐Lee M, Kuhn P, Wilton J, Iyer R, Abou‐Alfa GK. Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Oncologist 2020; 25:e1825-e1836. [PMID: 32548867 PMCID: PMC8186405 DOI: 10.1634/theoncologist.2020-0521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 05/31/2020] [Indexed: 12/20/2022] Open
Abstract
LESSONS LEARNED Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib. BACKGROUND Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models. METHODS This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics. RESULTS In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome. CONCLUSION Enzalutamide is ineffective in HCC; further development is not supported by this study.
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Affiliation(s)
- James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Robin K. Kelley
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of CaliforniaSan FranciscoCaliforniaUSA
| | - Benjamin Tan
- Department of Medicine, Washington UniversitySt. LouisMissouriUSA
| | - Marinela Capanu
- Department of Epidemiology‐Biostatistics, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Gian Kinh Do
- Department of Radiology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Joanne F. Chou
- Department of Epidemiology‐Biostatistics, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Christine S. Ferrer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Chayma Boussayoud
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Kerri Muenkel
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Hooman Yarmohammadi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Imane El Dika
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Danny N. Khalil
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Carmen Ruiz
- University of Southern California USC Michelson CenterLos AngelesCaliforniaUSA
| | | | - Peter Kuhn
- University of Southern California USC Michelson CenterLos AngelesCaliforniaUSA
| | - John Wilton
- Department of Medicine, Roswell Park Cancer InstituteBuffaloNew YorkUSA
| | - Renuka Iyer
- Department of Medicine, Roswell Park Cancer InstituteBuffaloNew YorkUSA
| | - Ghassan K. Abou‐Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical CollegeNew YorkNew YorkUSA
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Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2020; 149:1-61. [PMID: 33579421 PMCID: PMC8796122 DOI: 10.1016/bs.acr.2020.10.001] [Citation(s) in RCA: 527] [Impact Index Per Article: 105.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.
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Affiliation(s)
- Saranya Chidambaranathan-Reghupaty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
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42
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Zhang W, Liu F, Huang J, Guo X, Dong W, Wei S, Li L, Zhu X, Zhou W, Liu H. Effect of menopausal status on the survival and recurrence of sex-classified hepatocellular carcinoma after liver resection: a case-matched study with propensity score matching. Aging (Albany NY) 2020; 12:25895-25915. [PMID: 33232278 PMCID: PMC7803575 DOI: 10.18632/aging.202155] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 09/24/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To investigate the impact of menopausal status on the prognosis for sex-classified Hepatocellular carcinoma (HCC) and to establish prognostic nomograms for patients after liver resection. RESULTS After propensity score matching (PSM), statistically significant differences in both overall survival (OS) and recurrence-free survival (RFS) were found between men and women HCC patients. Based on Cox regression analysis, these differences were evident in the normal menstruation (N) group expanded with male patients, but not in either the expanded postmenopausal (P) or intermediate (I) groups. Sex disparity was also apparent in the recurrence-free survival (RFS) of the total HCC patients. Integrated with independent factors, nomograms for the OS and RFS of the expanded N group showed higher C-indices of 0.773 and 0.724, respectively, than those of nomograms for the total patients and BCLC stage (P<0.001). CONCLUSION Sex disparity appears to affect both the survival and recurrence of HCC only in normal menstruation women and their matched men. For predicting survival, prognostic nomograms derived from the expanded N group of HCC patients were more accurate for patients with the same clinical conditions. METHODS The patients (390 females and 1920 males), who underwent curative liver resection for HCC during 2008 to 2012, were screened. The 390 women were divided into three groups: normal menstruation, intermediate, and postmenopausal. To overcome selection bias, the three groups of females were matched with males at a ratio of 1:2, using propensity score matching. Based on further Cox regression analysis, independent factors were integrated into nomograms for OS and RFS by R rms. The accuracy and discrimination of the nomograms were evaluated by the C-index, calibration curve, and decision curve analysis.
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Affiliation(s)
- Wenli Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Fuchen Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Jian Huang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Xinggang Guo
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.,Changhai Hospital, Second Military Medical University, Shanghai 200438, China
| | - Wei Dong
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Shuxun Wei
- The First Department of General Surgery, Changzheng Hospital, Second Military Medical University and Naval Medical University, Shanghai 200438, China
| | - Li Li
- Department of Nephrology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiuli Zhu
- Department of Gastroenterology, Anhui Provincial Hospital, University of Science and Technology of China, Hefei, Anhui, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
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43
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Ringlander J, Skoglund C, Prakash K, Andersson ME, Larsson SB, Tang KW, Rydell GE, Abrahamsson S, Castedal M, Norder H, Hellstrand K, Lindh M. Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA. J Viral Hepat 2020; 27:1162-1170. [PMID: 32592629 DOI: 10.1111/jvh.13356] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/09/2020] [Accepted: 06/15/2020] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Integration of HBV DNA into the human genome may contribute to oncogenesis and to the production of the hepatitis B surface antigen (HBsAg). Whether integrations contribute to HBsAg levels in the blood is poorly known. Here, we characterize the HBV RNA profile of HBV integrations in liver tissue in patients with chronic HBV infection, with or without concurrent hepatitis D infection, by transcriptome deep sequencing. Transcriptomes were determined in liver tissue by deep sequencing providing 200 million reads per sample. Integration points were identified using a bioinformatic pipeline. Explanted liver tissue from five patients with end-stage liver disease caused by HBV or HBV/HDV was studied along with publicly available transcriptomes from 21 patients. Almost all HBV RNA profiles were devoid of reads in the core and the 3' redundancy (nt 1830-1927) regions, and contained a large number of chimeric viral/human reads. Hence, HBV transcripts from integrated HBV DNA rather than from covalently closed circular HBV DNA (cccDNA) predominated in late-stage HBV infection, in particular in cases with hepatitis D virus co-infection. The findings support the suggestion that integrated HBV DNA can be a significant source of HBsAg in humans.
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Affiliation(s)
- Johan Ringlander
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Catarina Skoglund
- The Transplant Institute, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.,Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kasthuri Prakash
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria E Andersson
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon B Larsson
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ka-Wei Tang
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gustaf E Rydell
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sanna Abrahamsson
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria Castedal
- The Transplant Institute, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.,Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Heléne Norder
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases. Sci Rep 2020; 10:4435. [PMID: 32157118 PMCID: PMC7064516 DOI: 10.1038/s41598-020-61298-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 02/24/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor in China. In the present study, we aimed to construct and verify a prediction model of recurrence in HCC patients using databases (TCGA, AMC and Inserm) and machine learning methods and obtain the gene signature that could predict early relapse of HCC. Statistical methods, such as feature selection, survival analysis and Chi-Square test in R software, were used to analyze and select mutant genes related to disease free survival (DFS), race and vascular invasion. In addition, whole-exome sequencing was performed on 10 HCC patients recruited from our center, and the sequencing results were compared with the databases. Using the databases and machine learning methods, the prediction model of recurrence was constructed and optimized, and the selected mutant genes were verified in the test group. The accuracy of prediction was 74.19%. Moreover, these 10 patients from our center were used to verify these mutant genes and the prediction model, and a success rate of 80% was achieved. Collectively, we discovered recurrence-related genes and established recurrence prediction model of recurrence for HCC patients, which could provide significant guidance for clinical prediction of recurrence.
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45
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Kong F, Kong D, Yang X, Yuan D, Zhang N, Hua X, You H, Zheng K, Tang R. Integrative analysis of highly mutated genes in hepatitis B virus-related hepatic carcinoma. Cancer Med 2020; 9:2462-2479. [PMID: 32017470 PMCID: PMC7131865 DOI: 10.1002/cam4.2903] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 01/15/2020] [Accepted: 01/21/2020] [Indexed: 12/14/2022] Open
Abstract
Gene mutation is responsible for the development of hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) infection; however, the characteristics and associated biological functions of highly mutated genes, in which the mutation frequencies are at least 5% in HCC patients with HBV infection, are not clearly evaluated. In the study, we analyzed the information regarding somatic mutation obtained by whole‐exome sequencing in 280 HBV‐related HCC tissues from public databases and published studies. Via integrative analysis, 78 genes, including TP53, TTN, MUC16, CTNNB1, and PCLO were summarized as highly mutated genes, and some of these mutated genes were further identified as cancer driver genes. Besides, we discovered that the highly mutated genes were enriched with various biological functions and pathways. The expression of many of highly mutated genes was found to be significantly altered in HBV‐related HCC, and several highly mutated genes were related to a variety of clinical factors and associated with the poor survival of the disease. Taken together, these results could enrich our understanding of highly mutated genes and their relationships with HBV‐related HCC. Some of the identified highly mutated genes might be used as novel biomarkers of disease prognosis, or as molecular targets for the treatment of HCC with HBV infection.
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Affiliation(s)
- Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Dongchen Yuan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Ning Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Xuan Hua
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China.,National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China.,National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China
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46
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Zhao L, Hu H, Gustafsson JÅ, Zhou S. Nuclear Receptors in Cancer Inflammation and Immunity. Trends Immunol 2020; 41:172-185. [PMID: 31982345 DOI: 10.1016/j.it.2019.12.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 12/10/2019] [Accepted: 12/11/2019] [Indexed: 02/05/2023]
Abstract
Members of the nuclear receptor (NR) superfamily orchestrate cellular processes that can impact on numerous cancer hallmarks. NR activity plays important roles in the tumor microenvironment by controlling inflammation and immune responses. We summarize recent insights into the diverse mechanisms by which NR activity can control tumor inflammation, the roles of different NRs in modulating tumor immunity, and the biological features of immune cells that express specific NRs in the context of cancer. NR-dependent alterations in tumor inflammation and immunity may be amenable to pharmacological manipulation and offer new clues regarding the development of novel cancer therapeutic regimens.
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Affiliation(s)
- Linjie Zhao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education (MOE), and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, PR China
| | - Hongbo Hu
- Department of Rheumatology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, PR China
| | - Jan-Åke Gustafsson
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Center for Medical Innovation, Department of Biosciences and Nutrition at Novum, Karolinska Institute, Stockholm, Sweden.
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education (MOE), and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, and Collaborative Innovation Center, Chengdu, PR China.
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47
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Yang Z, Chen J, Xie H, Liu T, Chen Y, Ma Z, Pei X, Yang W, Li L. Androgen receptor suppresses prostate cancer metastasis but promotes bladder cancer metastasis via differentially altering miRNA525-5p/SLPI-mediated vasculogenic mimicry formation. Cancer Lett 2019; 473:118-129. [PMID: 31843555 DOI: 10.1016/j.canlet.2019.12.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022]
Abstract
Early studies suggest that the androgen receptor (AR) may play differential roles in influencing prostate cancer (PCa) and bladder cancer (BCa) metastasis, but the underlying mechanisms remain unclear. Here, we found that the AR might function via differentially altering vasculogenic mimicry (VM) formation to either decrease PCa metastasis or increase BCa metastasis. Mechanism dissection showed that the AR could differentially alter the expression of the VM marker SLPI through miR-525-5p to regulate SLPI; moreover, it could either increase miR-525-5p transcription in PCa or decrease it in BCa via binding to different androgen-response-elements (AREs) located at different positions in the miR-525 precursor promoter. Further, results from liquid chromatography-mass spectrometry (LC-MS) showed that the co-factors of AR in PCa and BCa are NFIX and HDAC2, respectively. Together, these results provide the first detailed mechanism of how the AR can differentially alter PCa and BCa metastasis; thus, targeting the newly identified AR-miR-525-5p-SLPI axis may help suppress metastasis.
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Affiliation(s)
- Zhao Yang
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jiaqi Chen
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hongjun Xie
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Tianjie Liu
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yule Chen
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Zhenkun Ma
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinqi Pei
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenjie Yang
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Lei Li
- Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
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Cheng YW, Chen KW, Kuo HC, Kuo CH, Lin WH, Chen PJ, Yeh SH. Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes. Int J Obes (Lond) 2019; 43:2469-2479. [PMID: 31455870 DOI: 10.1038/s41366-019-0431-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 04/16/2019] [Accepted: 07/08/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. METHODS Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. RESULTS The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. CONCLUSIONS Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC.
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Affiliation(s)
- Ya-Wen Cheng
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Kai-Wei Chen
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Han-Chun Kuo
- The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Ching-Hua Kuo
- The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, 100, Taiwan.,School of Pharmacy, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Wei-Hsiang Lin
- NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Pei-Jer Chen
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan.,NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan. .,NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 100, Taiwan.
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Shang N, Wang H, Bank T, Perera A, Joyce C, Kuffel G, Zilliox MJ, Cotler SJ, Ding X, Dhanarajan A, Breslin P, Qiu W. Focal Adhesion Kinase and β-Catenin Cooperate to Induce Hepatocellular Carcinoma. Hepatology 2019; 70:1631-1645. [PMID: 31069844 PMCID: PMC6819211 DOI: 10.1002/hep.30707] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 05/02/2019] [Indexed: 12/17/2022]
Abstract
There is an urgent need to understand the molecular signaling pathways that drive or mediate the development of hepatocellular carcinoma (HCC). The focal adhesion kinase (FAK) gene protein tyrosine kinase 2 is amplified in 16.4% of The Cancer Genome Atlas HCC specimens, and its amplification leads to increased FAK mRNA expression. It is not known whether the overexpression of FAK alone is sufficient to induce HCC or whether it must cooperate in some ways with other oncogenes. In this study, we found that 34.8% of human HCC samples with FAK amplification also show β-catenin mutations, suggesting a co-occurrence of FAK overexpression and β-catenin mutations in HCC. We overexpressed FAK alone, constitutively active forms of β-catenin (CAT) alone, or a combination of FAK and CAT in the livers of C57/BL6 mice. We found that overexpression of both FAK and CAT, but neither FAK nor CAT alone, in mouse livers was sufficient to lead to tumorigenesis. We further demonstrated that FAK's kinase activity is required for FAK/CAT-induced tumorigenesis. Furthermore, we performed RNA-sequencing analysis to identify the genes/signaling pathways regulated by FAK, CAT, or FAK/CAT. We found that FAK overexpression dramatically enhances binding of β-catenin to the promoter of androgen receptor (AR), which leads to increased expression of AR in mouse livers. Moreover, ASC-J9, an AR degradation enhancer, suppressed FAK/CAT-induced HCC formation. Conclusion: FAK overexpression and β-catenin mutations often co-occur in human HCC tissues. Co-overexpression of FAK and CAT leads to HCC formation in mice through increased expression of AR; this mouse model may be useful for further studies of the molecular mechanisms in the pathogenesis of HCC and could lead to the identification of therapeutic targets.
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Affiliation(s)
- Na Shang
- Departments of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Hao Wang
- Departments of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Thomas Bank
- Departments of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Aldeb Perera
- Departments of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Cara Joyce
- Departments of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Gina Kuffel
- Departments of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Michael J. Zilliox
- Departments of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Scott J. Cotler
- Departments of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Xianzhong Ding
- Departments of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Asha Dhanarajan
- Departments of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Peter Breslin
- Departments of Molecular/Cellular Physiology and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL
| | - Wei Qiu
- Departments of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL,Correspondence: Wei Qiu, Ph.D., Department of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, 2160 S. First Avenue., Bldg. 112, Rm. 338, Maywood, IL 60153, , Tel.: +1-708-327-8191
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Qiu W. REPLY. Hepatology 2019; 70:1495-1496. [PMID: 31297851 DOI: 10.1002/hep.30845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Wei Qiu
- Departments of Surgery and Cancer Biology, Loyola University Chicago, Maywood, IL
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