Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b.
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.
Arora
Payal
P
Division of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Kim
Eun-Ok
EO
Jung
Jin Kyu
JK
Jang
Kyung Lib
KL
D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014758:Viral Core Proteins / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
D015820:Cadherins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D017931:DNA Primers; D012333:RNA, Messenger; D012097:Repressor Proteins; D014758:Viral Core Proteins; D000097584:DNA Methyltransferase 3B; C069130:nucleocapsid protein, Hepatitis C virus; C000619380:DNMT1 protein, human