title: Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice.
abstract: Although the activation of Ras pathway is frequently observed in human hepatocellular carcinoma (HCC), the in vivo role of Ras activation in HCC initiation and progression is underdetermined. To test the consequence of Kras activation in hepatocyte, we generated a hepatocyte-specific Kras(G12D) transgenic mouse strain and observed spontaneous development of HCC in these mice. Remarkably, HBV X protein (HBx) expression significantly promotes the formation and malignant progression of Kras(G12D)-driven HCC as shown with the accelerated tumor onset, the increased tumor burden and the more poorly differentiated lesions. At the cellular level, concomitant expression of Kras(G12D) and HBx results in a robust increase in hepatocellular proliferation. We reveal that the Akt, MAPK, p53 and TGF-β pathways are deregulated in the Kras(G12D)-driven HCCs. Also, the dysregulation is more pronounced in the HCCs developed in Kras(G12D) and HBx double transgenic mice. In addition, the altered expressions of β-catenin, CD44 and E-cadherin are only observed in the Kras(G12D) and HBx double transgenic mice. These results demonstrate a crucial role of Ras activation in hepatocellular carcinogenesis and the functional synergy between Kras(G12D) and HBx in HCC initiation and progression. The novel genetic mouse models that closely recapitulate the histopathologic progression and molecular alterations of human HCC may potentially facilitate the future therapeutic studies.
authors.affiliation: 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Ye
authors.affiliation: 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: B-J
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Tan
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai, China.
authors.forename: W-P
authors.initials: WP
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Teng
authors.affiliation: 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)