title: IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer mortality. Prognosis of this disease largely depends on its stage. An Enlarged liver, due to dysplasia, may be a critical point in the multi-step progression to HCC. The mechanism underlying hepatomegaly in human and mouse models are poorly understood. We previously reported we observed enlarged liver in hepatitis B virus X protein (HBx) expressing mice (HBx mice). Here we identify the critical role of HBx induced IGF-II in hepatomegaly in mice and abnormal cell growth in human hepatoma cells. We found that HBx induced IGF-II is essential to induce epithelial-mesenchymal transition (EMT) through loss of E-cadherin. In mouse liver, loss of E-cadherin was mediated by post-translational regulation, at least in part, by protease and SUMOylation not by transcriptional regulation. In contrast, in hepatoma cell line (HepG2 cells) Akt signal pathway controls the mRNA expression level of EMT-related transcription factors, especially Twist, in addition to post- translational modification through SUMOylation. Thus, IGF-II-mediated loss of E-cadherin is central in developing hepatomegaly in mice and abnormal cell growth in the hepatoma cell line. HBx induced IGF-II represents a potential biomarker, which is also a therapeutic target in HCC.
authors.affiliation: Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea.|Present address: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hye-Lin
authors.initials: HL
authors.lastname: Ha
authors.affiliation: Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Taeho
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: In Seon
authors.initials: IS
authors.lastname: Bak
authors.affiliation: Department of Molecular & Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA, USA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Erikson
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Republic of Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
mesh_terms: D000818:Animals; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D064200:Cdh1 Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006529:Hepatomegaly / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007335:Insulin-Like Growth Factor II
keywords: IGF-II; SUMOylation; epithelial-mesenchymal transition; hepatitis B virus X protein; hepatocellular carcinoma