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Pathological Implications of Hepatitis B Viral DNA Integration Into Host Cells

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Pathological Implications of Hepatitis B Viral DNA Integration Into Host Cells Article Gene and Gene Editing Copyright © 2015 American Scientific Publishers All rights reserved Vol. 1, 59–66, 2015 Printed in the United States of America www.aspbs.com/gge Pathological Implications of Hepatitis B Viral DNA Integration Into Host Cells Qian Yang1 2†, Yunzhi Pan2†,AliceS.S.Li3, Jia Zhang4,LiXiao2, and Pierre Sirois5 ∗ 1Department of Pathology, Kunming First People’s Hospital, Kunming, Yunnan, China 2Laboratory of Molecular Medicine, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China 3University of Waterloo, 200 University Ave W, Waterloo, ON, Canada, N2L 3G1 4Novartis Institute of Genomic Functional Study, San Diego, CA 92131, USA 5CHUL Research Center, Laval University, Quebec, Canada G1V 4G2 Infections with Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the main causes of human hepatocellular carci- noma HCC in many Asian countries. Viral DNA integration into the chromosomes of hepatic cells has been exclusively observed in HCC following chronic HBV infection. As the carcinogenesis is a slow and complicated process, it may be attributed to the activation of oncogenes, inactivation of tumor suppressor genes, and overexpression of viral genes by HBV DNA integration. Both HBV and HCV infections show individual and ethnic differences, it thus seems that where and how frequent the viral DNA integrated into hepatic chromosomes is of great relevance on its carcinogenicity. Better understanding of the pathologies following viral DNA integration has high clinical implications such as in the prevention, diagnosis, therapy, and prognosisIP: of 192.168.39.211 HCC in HBV infected On: Fri, individuals. 01 Oct 2021 Newly 06:32:53 developed technologies applied in HCC research have promising values. OneCopyright: of these technologies American Scientific is circulating Publishers DNA assay that may become a useful tool in studying both the viral DNA integration and the generalDelivered mutation by Ingenta load in the liver. Another technology is the engineered nuclease such as zinc finger nuclease and TAL nuclease. These nucleases may be used in slowing down or block the viral DNA integration process, thereby preventing and even treating HBV related HCC. KEYWORDS: HBV Integration, HCC, Hepatitis B, Carcinogenesis. INTRODUCTION closed circular supercoiled DNA (cccDNA) molecule. The Hepatitis virus and human hepatocellular carcinoma circularity of HBV DNA is maintained by its 5 cohesive (HCC) have a close relationship. Infections with Hepati- termini. The cccDNA is the original template that HBV tis B virus and hepatitis C virus are thought to be the replicates in hepatic cells. Transcripts are polyadenylated main causes of HCC in many Asian countries as docu- and transported to the cytoplasm where they are trans- mented by an increasing number of epidemiological data.1 lated into the viral nucleocapsid and precore antigen. HBV An epidemiological survey suggested that the main cause DNA has a very compact coding organization with four of HCC in China is hepatitis virus infection (mainly HBV partially overlapping open reading frames (ORFs) that are and HCV) with HBV contributing to 75–85% cases of the translated into seven known proteins: pre-S1, pre-S2, S, total amount of HCCs.2 pre-C, C, P, X protein and probably some other unknown HBV virion DNA is a relaxed circular, partially duplex products. The discovery of HBV DNA integration into the molecule of 3.2 kb. In the nucleus of infected cells, host cell genome is a milestone in HCC genetics research. when the second-strand DNA synthesis is completed, the During the course of chronic hepatitis B infection, HBV gaps in both strands are repaired to yield a covalently DNA randomly integrates into the hepatic cell genome at low frequency. The viral DNA integration usually leads the host gene to replacement, copy reverse, or deletion, etc.; ∗ Author to whom correspondence should be addressed. sequentially, it may influence genes involved in genetic E-mail: [email protected] †These two authors contributed equally to this work. reparation, cell cycling, cell differentiation and apopto- Received: 5 January 2014 sis of the host. These genetic changes may consequently Accepted: 25 January 2014 lead to carcinogenesis. This paper summarizes the present Gene Gene Edit. 2015, Vol. 1, No. 1 2376-3949/2015/1/059/008 doi:10.1166/gge.2015.1008 59 Pathological Implications of Hepatitis B Viral DNA Integration Into Host Cells Yang et al. progress of HBV integration into host cells and discusses the carcinogenesis effect of the HBV DNA integration. HBV INTEGRATION IN HCC An increasing number of data on HBV DNA integration into host cells suggest its possible relationship with liver carcinogenesis. HCC carcinogenesis is a complicated and relatively slow process in which HBV DNA continuously integrates into host chromosomes in the period of acute and chronic hepatitis or in HBV carriers. In a study of 68 cases of HCC, the integration of HBV DNA in host hepatic cells was detected in 61 cases.3 The viral insertion site was spread over all chromo- somes except chromosomes 13, X, and Y. The genes involved include oncogenes, anti-oncogenes, apoptosis- related genes, and genes coding unknown proteins. Some other genes such as human telomerase reverse transcrip- tase (hTERT) gene, calcium signaling related gene, 60 s ribosomal protein encoding gene, platelet derived growth factor gene, and mixed lineage leukemia (MLL) encoding gene sites were interrupted by HBV DNA integration in selected cases. Another study with 40 HCC cases also showed a high percentage of HBV DNA integration into hepatic cells, in which 68 HBV integration loci were identified in 34 cases.4 These involved loci mostly related to the cell cycle and gene controlling, suchIP:as: 192.168.39.211 cell cycle control- On: Fri, 01 Oct 2021 06:32:53 ling gene CDKN2C; apoptosis-relatedCopyright: gene PAWR, American NTNl, Scientific Publishers MAPK8IP2, TNFsFlA, TNFRsFlA, and N7ITNl;Delivered signal by Ingenta conduction gene GNATl, MAPKl, and MAPK8 IP2; tran- scription related gene MTFl, MAML3, ROCK2, RAB5A, NSPCI, TBXl, and wTl; protein composition gene EIF5 and TINPl; DNA repairment gene (GTSEl); and protein degeneration and transfer gene RAB5A, etc. Among them, MLL4, GNATl, and FNl are most frequently identified in different specimens of selected cases. The chromosomes and genes involved in HBV inte- gration are widespread and may not be selective. Tamori et al. studied 15 HCC cases and detected the gene inte- gration site in ras-responsive element binding protein 1, Figure 1. Carcinogenesis of hepatocellular carcinoma and calmodulin 1, mixed lineage leukemia 2 (MLL2).5 Tokino HBV infection. Hepatocelluar carcinomas are associated with et al. reported that HBV DNA could integrate in chro- chronic HBV infection. Following HBV infection, most of the patients can completely recover from acute hepatitis by mosomes including chromosome X; at chromosome 11 removing all HBV with host immunity. However, 10–20% of the 6 and 17, HBV integration was detected at a higher rate. infected individuals become HBV carrier or chronic patients. The HBV DNA integration at human telomerase reverse The process of HBV DNA integration into host hepatic cells transcriptase (hTERT) gene site was identified in 2 HCC thus occurs over years during viral replication and hepatic cases.7 Interestingly, in cervix cancer, human papillary cell proliferation. Some of the viral DNA integration may have little or no carcinogenic effects, whereas mutagenic and car- virus (HPV) integration into hTERT gene loci was also cinogenic effects are significant when pro-oncogenes are acti- detected. It appears that although HBV DNA may integrate vated, cancer suppressor genes are inhibited, and certain viral into the hepatic cell genome randomly in HCCs, some par- genes are overexpressed. ticular genes may play an important role in carcinogenesis following HBV integration (Fig. 1). change the expression of oncogene, anti-oncogene and It was suggested that many integration events occur in micro RNA. HBV DNA integration can induce wide-range unsteady human genome or genes surrounding it.8 Integra- genetic changes in the host genome including chromosome tion also takes place near the cancer-related genes and may deletion, translocation, fusion gene transcripts, genomic 60 Gene Gene Edit. 1, 59–66, 2015 Yang et al. Pathological Implications of Hepatitis B Viral DNA Integration Into Host Cells DNA amplification, and genomic instability. Some of the cell carcinoma are more closely related to each other in integration loci are tabulated in Table I. chronic as compared to acute viral hepatitis. In an 18 year Recently, a whole-genome sequencing of 4 HCC follow up study, Giacchino investigated 325 children car- patients was performed; a total of 255 HBV integra- rying HBV; three of them converted to chronic hepatitis tion sites were identified in 4 HCC which revealed and then to hepatic cell carcinoma after 6–11 years, and the widespread viral integration events. They observed HBV DNA integration was detected in one of these three a diverse collection of genomic perturbations near viral patients. integration sites, including direct gene disruption, viral promoter-driven human transcription, viral-human tran- Chronic Hepatitis script fusion, and DNA copy number alteration. Such Viral DNA integration is more frequently identified in widespread random viral integration will likely increase chronic hepatitis patients studied. In a study of 16 chronic carcinogenic opportunities in HBV-infected individuals. hepatitis, Takada et al. detected random integration of The initial HBV integration reports have likely been under- HBV DNA in 15 cases by Southern blot in which all estimated by previous PCR-based approaches.9 integrants had some flanking sequence DNA deletion and some had gene rearrangements.14 In another report, Acute Hepatitis Murakami et al. reported the HBV DNA integration in all In a study with 19 cases of acute hepatitis, HBV DNA of the 12 chronic hepatitis cases.10 integrations were detected in 3 cases in which one integra- The clinical consequences of viral DNA integration are tion site was in the tumor necrosis factor (TNF)-induced of great importance.
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