Journal
ONCOTARGET
Volume 7, Issue 35, Pages 56944-56957Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10922
Keywords
hepatocellular carcinoma; hepatitis B virus X protein; IGF-II; epithelial-mesenchymal transition; SUMOylation
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Funding
- R&D Convergence Program of the National Research Council of Science & Technology (NST) of the Republic of Korea [CAP-15-03-KRIBB, CAP-16-03-KRIBB]
- Bio and Medical Technology Development Program of the Ministry of Science, ICT and Future Planning (MSIP) of Korea [NRF-2014M3A9B5073938]
- National Research Foundation of Korea [2014M3A9B5073938] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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