{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:27:25Z","timestamp":1790519245452,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["98-2314-B-182A-065-MY2"],"award-info":[{"award-number":["98-2314-B-182A-065-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["106-2314-B-182A-148-MY1"],"award-info":[{"award-number":["106-2314-B-182A-148-MY1"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T\/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I\/sW196*, has not been studied. We constructed plasmids harboring rtM204I\/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I\/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for c-fos, increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 (XBP1) splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated MGST2 and HIF1A, and downregulated transforming growth factor beta-induced (TGFbi), were unveiled by cDNA microarray and validated by RT-qPCR. The TGFbi alteration occurred in transformants with wild type or mutated HBV. The altered MGST2 and HIF1A were found only with mutated HBV. The rtM204I\/sW196* preS\/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including MGST2, HIF1A, and TGFbi. Downregulated TGFbi may be a common mechanism for oncogenicity in HBV surface truncation mutants.<\/jats:p>","DOI":"10.3390\/ijms21176366","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T09:29:28Z","timestamp":1599038968000},"page":"6366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hepatitis B Virus preS\/S Truncation Mutant rtM204I\/sW196* Increases Carcinogenesis through Deregulated HIF1A, MGST2, and TGFbi"],"prefix":"10.3390","volume":"21","author":[{"given":"Ming-Wei","family":"Lai","sequence":"first","affiliation":[{"name":"Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan"},{"name":"Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan"},{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kung-Hao","family":"Liang","sequence":"additional","affiliation":[{"name":"Medical Research Department, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau-Ting","family":"Yeh","sequence":"additional","affiliation":[{"name":"Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan"},{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJM199807093390201","article-title":"A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group","volume":"339","author":"Lai","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1053\/gast.2000.8559","article-title":"Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group","volume":"119","author":"Liaw","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1053\/jhep.2001.25084","article-title":"Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: Results after 3 years of therapy","volume":"33","author":"Leung","year":"2001","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1111\/j.1440-1746.2004.03428.x","article-title":"Four years of lamivudine treatment in Chinese patients with chronic hepatitis B","volume":"19","author":"Chang","year":"2004","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0168-8278(03)00155-7","article-title":"Results of lamivudine trials in Asia","volume":"39","author":"Liaw","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1056\/NEJMoa033364","article-title":"Lamivudine for patients with chronic hepatitis B and advanced liver disease","volume":"351","author":"Liaw","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.20760","article-title":"Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine","volume":"42","author":"Papatheodoridis","year":"2005","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/hep.26180","article-title":"Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection","volume":"58","author":"Hosaka","year":"2013","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1053\/j.gastro.2014.03.048","article-title":"Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B\u2014A nationwide cohort study","volume":"147","author":"Wu","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1365-2893.2004.00564.x","article-title":"High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance","volume":"11","author":"Andreone","year":"2004","journal-title":"J. Viral. Hepat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1111\/j.1365-2036.2008.03816.x","article-title":"Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma","volume":"28","author":"Sung","year":"2008","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8373","DOI":"10.3748\/wjg.v19.i45.8373","article-title":"Antiviral drug resistance increases hepatocellular carcinoma: A prospective decompensated cirrhosis cohort study","volume":"19","author":"Li","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1053\/j.gastro.2009.08.063","article-title":"Hepatitis B virus resistance to nucleos(t)ide analogues","volume":"137","author":"Zoulim","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1177\/135965350801300701","article-title":"The oncogenic potential of hepatitis B virus rtA181T\/surface truncation mutant","volume":"13","author":"Lai","year":"2008","journal-title":"Antivir. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1073\/pnas.87.8.2970","article-title":"A trans-activator function is generated by integration of hepatitis B virus preS\/S sequences in human hepatocellular carcinoma DNA","volume":"87","author":"Caselmann","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/343457a0","article-title":"The preS2\/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator","volume":"343","author":"Kekule","year":"1990","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1177\/135965350901400216","article-title":"Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy","volume":"14","author":"Lai","year":"2009","journal-title":"Antivir. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1093\/infdis\/jiv547","article-title":"Peginterferon is superior to nucleos(t)ide analogues for prevention of hepatocellular carcinoma in chronic hepatitis B","volume":"213","author":"Liang","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1038\/oncsis.2016.77","article-title":"Hepatocarcinogenesis in transgenic mice carrying hepatitis B virus pre-S\/S gene with the sW172* mutation","volume":"5","author":"Lai","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Huang, S.F., Chen, Y.T., Lee, W.C., Chang, I.C., Chiu, Y.T., Chang, Y., Tu, H.C., Yuh, C.H., Matsuura, I., and Shih, L.Y. (2014). Identification of transforming hepatitis B virus S gene nonsense mutations derived from freely replicative viruses in hepatocellular carcinoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089753"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jhep.2011.06.028","article-title":"Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases","volume":"56","author":"Lee","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.bbadis.2014.03.007","article-title":"Dysregulation of the TGFBI gene is involved in the oncogenic activity of the nonsense mutation of hepatitis B virus surface gene sW182*","volume":"1842","author":"Jiang","year":"2014","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.virol.2016.11.007","article-title":"Stop codons in the hepatitis B surface proteins are enriched during antiviral therapy and are associated with host cell apoptosis","volume":"501","author":"Colledge","year":"2017","journal-title":"Virology"},{"key":"ref_25","unstructured":"(2020, June 01). \u201cExpression of MGST2 in cancer\u201d-Summary, The Human Protein Atlas. Available online: https:\/\/v15.proteinatlas.org\/ENSG00000085871-MGST2."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10112","DOI":"10.1038\/ncomms10112","article-title":"Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage","volume":"6","author":"Dvash","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/mc.20240","article-title":"Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers","volume":"45","author":"Savaraj","year":"2006","journal-title":"Mol. Carcinog."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nrc2809","article-title":"Eicosanoids and cancer","volume":"10","author":"Wang","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","unstructured":"(2020, June 01). \u201cHIF1A protein expression summary\u201d, The Human Protein Atlas. Available online: https:\/\/v15.proteinatlas.org\/ENSG00000100644-HIF1A."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1007\/s00018-019-03066-9","article-title":"Stabilization of E2-EPF UCP protein is implicated in hepatitis B virus-associated hepatocellular carcinoma progression","volume":"76","author":"Lim","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/bjc.2013.787","article-title":"HBx mutants differentially affect the activation of hypoxia-inducible factor-1alpha in hepatocellular carcinoma","volume":"110","author":"Liu","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1099\/0022-1317-78-6-1487","article-title":"The hepatitis B virus MHBst167 protein is a pleiotropic transactivator mediating its effect via ubiquitous cellular transcription factors","volume":"78","author":"Caselmann","year":"1997","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/mc.20167","article-title":"Loss of Betaig-h3 protein is frequent in primary lung carcinoma and related to tumorigenic phenotype in lung cancer cells","volume":"45","author":"Zhao","year":"2006","journal-title":"Mol. Carcinog."},{"key":"ref_34","first-page":"561","article-title":"BigH3 protein expression as a marker for breast cancer","volume":"21","author":"Calaf","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ygyno.2010.03.025","article-title":"Frequent promoter hypermethylation of TGFBI in epithelial ovarian cancer","volume":"118","author":"Kang","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_36","first-page":"6996","article-title":"Secreted and cell surface genes expressed in benign and malignant colorectal tumors","volume":"61","author":"Buckhaults","year":"2001","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0925-4439(02)00052-2","article-title":"Induction and expression of \u03b2ig-h3 in pancreatic cancer cells","volume":"1588","author":"Schneider","year":"2002","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12943-015-0335-z","article-title":"The role of TGFBI (\u03b2ig-H3) in gastrointestinal tract tumorigenesis","volume":"14","author":"Han","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_39","unstructured":"(2020, June 01). \u201cExpression of TGFBI in liver cancer\u201d, The Human Protein Atlas. Available online: https:\/\/v15.proteinatlas.org\/ENSG00000120708-TGFBI."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12985-018-0972-0","article-title":"The truncated mutant HBsAg expression increases the tumorigenesis of hepatitis B virus by regulating TGF-beta\/Smad signaling pathway","volume":"15","author":"Wang","year":"2018","journal-title":"Virol. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6366\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:05:48Z","timestamp":1760177148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6366"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,2]]},"references-count":40,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21176366"],"URL":"https:\/\/doi.org\/10.3390\/ijms21176366","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,2]]}}}