Research Papers:

IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice

Hye-Lin Ha _, Taeho Kwon, In Seon Bak, Raymond L. Erikson, Bo Yeon Kim and Dae-Yeul Yu

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Oncotarget. 2016; 7:56944-56957. https://doi.org/10.18632/oncotarget.10922

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Hye-Lin Ha1,2,5,*, Taeho Kwon1,*, In Seon Bak1, Raymond L. Erikson3, Bo Yeon Kim4, Dae-Yeul Yu1,2

1Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea

2Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon, Republic of Korea

3Department of Molecular & Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA, USA

4Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Republic of Korea

5Present address: Immune Activation Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

*Hye-Lin Ha and Taeho Kwon equally contributed to this research

Correspondence to:

Dae-Yeul Yu, email: dyyu10@kribb.re.kr

Bo Yeon Kim, email: bykim@kribb.re.kr

Keywords: hepatocellular carcinoma, hepatitis B virus X protein, IGF-II, epithelial-mesenchymal transition, SUMOylation

Received: January 25, 2016    Accepted: July 18, 2016    Published: July 29, 2016


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.

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