{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:15:51Z","timestamp":1787062551880,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T00:00:00Z","timestamp":1620432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["CMU109-ASIA-09"],"award-info":[{"award-number":["CMU109-ASIA-09"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.<\/jats:p>","DOI":"10.3390\/v13050862","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T02:54:58Z","timestamp":1620615298000},"page":"862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Yueh-Te","family":"Lin","sequence":"first","affiliation":[{"name":"Cancer Genome Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long-Bin","family":"Jeng","sequence":"additional","affiliation":[{"name":"Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Ling","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan"},{"name":"Epigenome Research Center, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ih-Jen","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5218-0571","authenticated-orcid":false,"given":"Chiao-Fang","family":"Teng","sequence":"additional","affiliation":[{"name":"Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan"},{"name":"Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular carcinoma","volume":"2","author":"Llovet","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7603\/s40681-016-0016-2","article-title":"Association of different types of liver disease with demographic and clinical factors","volume":"6","author":"Cheng","year":"2016","journal-title":"Biomedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1053\/j.gastro.2018.08.065","article-title":"Epidemiology and management of hepatocellular carcinoma","volume":"156","author":"Kulik","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_4","first-page":"394","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"887","DOI":"10.17219\/acem\/76750","article-title":"Risk factors of recurrence and poor survival in curatively resected hepatocellular carcinoma with microvascular invasion","volume":"29","author":"Zhou","year":"2020","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tampaki, M., Papatheodoridis, G.V., and Cholongitas, E. (2021). Intrahepatic recurrence of hepatocellular carcinoma after resection: An update. Clin. J. Gastroenterol.","DOI":"10.1007\/s12328-021-01394-7"},{"key":"ref_7","first-page":"2471","article-title":"Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide: Liver cancer attributable to hepatitis viruses worldwide","volume":"142","author":"Franceschi","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/S0140-6736(03)14964-1","article-title":"Hepatocellular carcinoma","volume":"362","author":"Llovet","year":"2003","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11630","DOI":"10.3748\/wjg.v20.i33.11630","article-title":"Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis","volume":"20","author":"Tarocchi","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mani, S.K.K., and Andrisani, O. (2018). Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells. Genes, 9.","DOI":"10.3390\/genes9030137"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev.mi.31.100177.002041","article-title":"The Genome of Hepatitis B Virus","volume":"31","author":"Robinson","year":"1977","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1056\/NEJM199712113372406","article-title":"Hepatitis B Virus Infection","volume":"337","author":"Lee","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1016\/S0002-9440(10)63599-7","article-title":"Different Types of Ground Glass Hepatocytes in Chronic Hepatitis B Virus Infection Contain Specific Pre-S Mutants that May Induce Endoplasmic Reticulum Stress","volume":"163","author":"Wang","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1111\/j.1440-1746.2008.05348.x","article-title":"Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection","volume":"23","author":"Su","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-014-0098-7","article-title":"The emerging role of hepatitis B virus Pre-S2 deletion mutant proteins in HBV tumorigenesis","volume":"21","author":"Su","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Teng, C.-F., Wu, H.-C., Su, I.-J., and Jeng, L.-B. (2020). Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma. Viruses, 12.","DOI":"10.3390\/v12090945"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3727\/096368916X694382","article-title":"Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma","volume":"26","author":"Teng","year":"2017","journal-title":"Cell Transplant."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lin, W.-L., Hung, J.-H., and Huang, W. (2020). Association of the Hepatitis B Virus Large Surface Protein with Viral Infectivity and Endoplasmic Reticulum Stress-mediated Liver Carcinogenesis. Cells, 9.","DOI":"10.3390\/cells9092052"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1053\/jhep.2001.21163","article-title":"Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection","volume":"33","author":"Fan","year":"2001","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1423-0127-16-84","article-title":"A pre-S gene chip to detect pre-S deletions in hepatitis B virus large surface antigen as a predictive marker for hepatoma risk in chronic hepatitis B virus carriers","volume":"16","author":"Shen","year":"2009","journal-title":"J. Biomed. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1365-2893.2006.00784.x","article-title":"Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection","volume":"14","author":"Choi","year":"2006","journal-title":"J. Viral Hepat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jcv.2016.06.018","article-title":"PreS deletion profiles of hepatitis B virus (HBV) are associated with clinical presentations of chronic HBV infection","volume":"82","author":"Li","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13573","DOI":"10.3748\/wjg.v20.i37.13573","article-title":"Novel approach to identifying the hepatitis B virus pre-S deletions associated with hepatocellular carcinoma","volume":"20","author":"Zhao","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1099\/jgv.0.000942","article-title":"Next-generation sequencing revealed divergence in deletions of the preS region in the HBV genome between different HBV-related liver diseases","volume":"98","author":"Jia","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1053\/j.gastro.2007.09.002","article-title":"Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients","volume":"133","author":"Chen","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s10620-012-2408-9","article-title":"Pre-S Mutation Is a Significant Risk Factor for Hepatocellular Carcinoma Development: A Long-Term Retrospective Cohort Study","volume":"58","author":"Sinn","year":"2012","journal-title":"Dig. Dis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100144","DOI":"10.1016\/j.jhepr.2020.100144","article-title":"Hepatitis B virus preS2\u039438\u201355 variants: A newly identified risk factor for hepatocellular carcinoma","volume":"2","author":"Cohen","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e8311","DOI":"10.1097\/MD.0000000000008311","article-title":"Pre-S deletions of hepatitis B virus predict recurrence of hepatocellular carcinoma after curative resection","volume":"96","year":"2017","journal-title":"Medicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/hep.29790","article-title":"Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection","volume":"68","author":"Yen","year":"2018","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14816","DOI":"10.1038\/s41598-018-33051-4","article-title":"A Next-Generation Sequencing-Based Platform for Quantitative Detection of Hepatitis B Virus Pre-S Mutants in Plasma of Hepatocellular Carcinoma Patients","volume":"8","author":"Teng","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Teng, C.-F., Tsai, H.-W., Li, T.-C., Wang, T., Wang, J., Shyu, W.-C., Wu, H.-C., Su, I.-J., and Jeng, L.-B. (2020). Detection of hepatitis B virus pre-S mutants in plasma by a next-generation sequencing-based platform determines their patterns in liver tissues. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234773"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Teng, C.F., Li, T.C., Huang, H.Y., Lin, J.H., Chen, W.S., Shyu, W.C., Wu, H.C., Peng, C.Y., Su, I.J., and Jeng, L.B. (2020). Next-generation sequencing-based quantitative detection of hepatitis B virus pre-S mutants in plasma predicts hepatocellular carcinoma recurrence. Viruses, 12.","DOI":"10.3390\/v12080796"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Teng, C.F., Li, T.C., Huang, H.Y., Chan, W.L., Wu, H.C., Shyu, W.C., Su, I.J., and Jeng, L.B. (2020). Hepatitis B virus pre-S2 deletion (nucleotide 1 to 54) in plasma predicts recurrence of hepatocellular carcinoma after curative surgical resection. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0242748"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Thedja, M.D., Muljono, D.H., Ie, S.I., Sidarta, E., Verhoef, J., and Marzuki, S. (2015). Genogeography and Immune Epitope Characteristics of Hepatitis B Virus Genotype C Reveals Two Distinct Types: Asian and Papua-Pacific. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132533"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13027-018-0179-4","article-title":"Quasispecies variant of pre-S\/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection","volume":"13","author":"Hatazawa","year":"2018","journal-title":"Infect. Agents Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1002\/cncr.25837","article-title":"A clustered ground-glass hepatocyte pattern represents a new prognostic marker for the recurrence of hepatocellular carcinoma after surgery","volume":"117","author":"Tsai","year":"2011","journal-title":"Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27724","DOI":"10.18632\/oncotarget.8388","article-title":"Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma","volume":"7","author":"Tsai","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1093\/carcin\/bgh207","article-title":"Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage","volume":"25","author":"Hsieh","year":"2004","journal-title":"Carcinogenesis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46384","DOI":"10.1074\/jbc.M403568200","article-title":"Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase","volume":"279","author":"Hung","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1002\/hep.22889","article-title":"Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis","volume":"49","author":"Yang","year":"2009","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Teng, C.-F., Hsieh, W.-C., Wu, H.-C., Lin, Y.-J., Tsai, H.-W., Huang, W., and Su, I.-J. (2015). Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122373"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1128\/JVI.02363-14","article-title":"Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis","volume":"89","author":"Teng","year":"2015","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/hep.20615","article-title":"Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes","volume":"41","author":"Wang","year":"2005","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/carcin\/bgr296","article-title":"Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus Pre-S2 mutants and its implication in hepatocarcinogenesis","volume":"33","author":"Wang","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23346","DOI":"10.18632\/oncotarget.8109","article-title":"Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability","volume":"7","author":"Yen","year":"2016","journal-title":"Oncotarget"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1158\/1541-7786.MCR-07-0098","article-title":"Hepatitis B virus pre-S2 mutant sur-face antigen induces degradation of cyclin-dependent kinase inhibitor p27Kip1 through c-Jun activation do-main-binding protein 1","volume":"5","author":"Hsieh","year":"2007","journal-title":"Mol. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12675","DOI":"10.1128\/JVI.01497-13","article-title":"Zinc-Dependent Interaction between JAB1 and Pre-S2Mutant Large Surface Antigen of Hepatitis B Virus and Its Implications for Viral Hepatocarcinogenesis","volume":"87","author":"Hsu","year":"2013","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/path.4531","article-title":"Hepatitis B virus pre-S2 mutant large surface protein inhibits DNA double-strand break repair and leads to genome instability in hepatocarcinogenesis","volume":"236","author":"Hsieh","year":"2015","journal-title":"J. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hung, J.H., Teng, Y.N., Wang, L.H.C., Su, I.J., Wang, C.C., Huang, W., Lee, K.H., Lu, K.Y., and Wang, L.H. (2011). Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028977"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2147\/JHC.S282818","article-title":"Increased Expression of Programmed Death Ligand 1 in Hepatocellular Carcinoma of Patients with Hepatitis B Virus Pre-S2 Mutant","volume":"7","author":"Teng","year":"2020","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-80935-5","article-title":"Increased infiltration of regulatory T cells in hepatocellular carcinoma of patients with hepatitis B virus pre-S2 mutant","volume":"11","author":"Teng","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1053\/j.gastro.2007.03.102","article-title":"Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients","volume":"132","author":"Fu","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1158\/1078-0432.CCR-08-1608","article-title":"Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma","volume":"15","author":"Gao","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.2147\/OTT.S110713","article-title":"Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients","volume":"9","author":"Gao","year":"2016","journal-title":"OncoTargets Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"246","DOI":"10.4143\/crt.2016.066","article-title":"Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma","volume":"49","author":"Jung","year":"2017","journal-title":"Cancer Res. Treat."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1034\/j.1600-065X.2001.1820104.x","article-title":"Control of T-cell activation by CD4+ CD25+ suppressor T cells","volume":"182","author":"Shevach","year":"2001","journal-title":"Immunol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","article-title":"Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation","volume":"192","author":"Freeman","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/path.4850","article-title":"Expression of a hepatitis B virus pre-S2 deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice","volume":"241","author":"Teng","year":"2017","journal-title":"J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.humpath.2013.10.039","article-title":"Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis","volume":"45","author":"Wu","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-46891-5","article-title":"Chemopreventive Effect of Phytosomal Curcumin on Hepatitis B Virus-Related Hepatocellular Carcinoma in A Transgenic Mouse Model","volume":"9","author":"Teng","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/carcin\/bgs365","article-title":"Histone deacetylase inhibitor suberoylanilide hydroxamic acid suppresses the pro-oncogenic effects induced by hepatitis B virus pre-S 2 mutant oncoprotein and represents a potential chemopreventive agent in high-risk chronic HBV patients","volume":"34","author":"Hsieh","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_63","first-page":"620","article-title":"Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice","volume":"21","author":"Huang","year":"1995","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7387","DOI":"10.1128\/jvi.71.10.7387-7392.1997","article-title":"Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum","volume":"71","author":"Xu","year":"1997","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/path.5102","article-title":"Intrahepatic hepatitis B virus large surface an-tigen induces hepatocyte hyperploidy via failure of cytokinesis","volume":"245","author":"Li","year":"2018","journal-title":"J. Pathol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:58:13Z","timestamp":1760162293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,8]]},"references-count":65,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["v13050862"],"URL":"https:\/\/doi.org\/10.3390\/v13050862","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,8]]}}}