title: HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice.
abstract: Hepatocellular carcinoma (HCC) affects males in a significantly higher proportion than females and is one of the human cancers etiologically related to viral factors. Many studies provide strong evidence of the direct role that hepatitis B virus (HBV) plays in hepatic carcinogenesis, but the functions of HBV surface antigen (HBsAg) and X protein (HBx) in hepatocarcinogenesis through direct or indirect mechanisms are still being debated. We generated two HBV gene knock-in transgenic mouse lines by homologous recombination. HBsAg and HBx genes were integrated into the mouse p21 locus. Both male and female p21-HBx transgenic mice developed HCC after the age of 18 months; however, male p21-HBsAg transgenic mice began to develop HCC 3 months earlier. The expression of a number of genes related to metabolism and genomic instability largely resembled the molecular changes during the development of HCC in humans. ER-beta (estrogen receptor-beta) was extremely up-regulated only in tumor tissues of male p21-HBsAg mice, providing genetic evidence that HBsAg might be the major risk factor affecting the gender difference in the causes of HCC. In conclusion, these mice might serve as good models for studying the different roles of HBsAg and HBx in early events of HBV-related hepatocarcinogenesis.
authors.affiliation: Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China.
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Cui
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Lv
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Dongping
authors.initials: D
authors.lastname: Wang
authors.forename: Yansong
authors.initials: Y
authors.lastname: Sun
authors.forename: Gengxi
authors.initials: G
authors.lastname: Hu
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Lang
authors.forename: Cuifen
authors.initials: C
authors.lastname: Huang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D047629:Estrogen Receptor beta; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000235:genetics; D012727:Sex Characteristics; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047629:Estrogen Receptor beta; D006514:Hepatitis B Surface Antigens; D011960:Receptors, Estrogen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein