Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b

• Published in: Cancer letters Vol. 261; no. 2; pp. 244 - 252
• Main Authors: Arora, Payal, Kim, Eun-Ok, Jung, Jin Kyu, Jang, Kyung Lib
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 18.03.2008; Elsevier Limited
• Subjects: Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell adhesion & migration; Cell Movement; Core; CpG Islands; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA Methyltransferase 3B; DNA Primers; E-cadherin; Enzymes; Fluorescent Antibody Technique; Gene expression; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Hepatitis; Hepatitis C virus; Hepatocellular carcinoma; Humans; Kinases; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Plasmids; Proteins; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Viral Core Proteins - metabolism; DNA methylation; Hepatocellular carcinoma; Hepatitis C virus; E-cadherin; Core
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2007.11.033

E-cadherin is a major cell adhesion molecule implicated as a potent tumor suppressor, which is frequently altered in human tumors including hepatocellular carcinoma. Here, we report that hepatitis C virus Core downregulates E-cadherin expression at the transcription level. This effect was abolished after treatment of 5′-Aza-2′dC, a specific inhibitor of DNA methyltransferase (DNMT). In addition, this repression was strongly correlated with hypermethylation of CpG islands of E-cadherin promoter via concerted action of both DNMT1 and 3b in Core-expressing cells. The decreased E-cadherin expression results in dramatic morphological changes in Core-expressing cells. In addition, Core-expressing cells aggregate poorly in suspension culture, reflecting their altered cell–cell interactions. The biological significance was further demonstrated by the increased collagen invasion ability of Core-expressing cells. Therefore, our finding suggests that Core plays a role in hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.