title: Hepatocarcinogenesis in transgenic mice carrying hepatitis B virus pre-S/S gene with the sW172* mutation.
abstract: Hepatitis B virus (HBV) carrying the rtA181T/sW172* mutation conferred cross-resistance to adefovir and lamivudine. Cell-based and clinical studies indicated that HBV carrying this mutation had an increased oncogenic potential. Herein, we created transgenic mouse models to study the oncogenicity of the HBV pre-S/S gene containing this mutation. Transgenic mice were generated by transfer of the HBV pre-S/S gene together with its own promoter into C57B6 mice. Four lines of mice were created. Two of them carried wild-type gene and produced high and low levels of HBV surface antigen (HBsAg) (TgWT-H and L). The other two carried the sW172* mutation with high and low intrahepatic expression levels (TgSW172*-H and L). When sacrificed 18 months after birth, none of the TgWT mice developed hepatocellular carcinoma (HCC), whereas 6/26 (23.1%) TgSW172*-H and 2/24 (8.3%) TgSW172*-L mice developed HCC (TgWT vs TgSW172*; P=0.0021). Molecular analysis of liver tissues revealed significantly increased expression of glucose-regulated protein 78 and phosphorylated extracellular signal-regulated kinases 1 in TgSW172* mice, and decreased expression of B-cell lymphoma-extra large in TgSW172*-H mice. Higher proportion of apoptotic cells was found in TgSW172*-H mice, accompanied by increased cyclin E levels, suggesting increased hepatocyte turnover. Combined analysis of complimentary DNA microarray and microRNA array identified microRNA-873-mediated reduced expression of the CUB and Sushi multiple domains 3 (CSMD3) protein, a putative tumor suppressor, in TgSW172* mice. Our transgenic mice experiments confirmed that HBV pre-S/S gene carrying the sW172* mutation had an increased oncogenic potential. Increased endoplasmic reticulum stress response, more rapid hepatocyte turnover and decreased CSMD3 expression contributed to the hepatocarcinogenesis.
authors.affiliation: Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.|Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.|Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: M-W
authors.initials: MW
authors.lastname: Lai
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: K-H
authors.initials: KH
authors.lastname: Liang
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.|Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: W-R
authors.initials: WR
authors.lastname: Lin
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: S-F
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: T-C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Linkou, Taiwan.|Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: C-T
authors.initials: CT
authors.lastname: Yeh