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Involvement of mi RNA ‐29a in epigenetic regulation of transforming growth factor‐β‐induced epithelial–mesenchymal transition in hepatocellular carcinoma
Author(s) -
Kogure Takayuki,
Kondo Yasuteru,
Kakazu Eiji,
Ninomiya Masashi,
Kimura Osamu,
Shimosegawa Tooru
Publication year - 2014
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12188
Subject(s) - dna methylation , epithelial–mesenchymal transition , epigenetics , dnmt1 , cancer research , methylation , cpg site , biology , dna methyltransferase , methyltransferase , transforming growth factor , dnmt3b , microrna , microbiology and biotechnology , chemistry , metastasis , gene expression , cancer , gene , genetics
Aim Epithelial–mesenchymal transition ( EMT ) is a crucial process during cancer invasion and metastasis, which is accompanied by the suppressed expression of E ‐cadherin initiated by stimuli such as transforming growth factor ( TGF )‐β. Recent studies have shown that the epigenetic regulation of E ‐cadherin could be an alternate mechanism of EMT induction in hepatocellular carcinoma ( HCC ). mi RNA ‐29a ( miR ‐29a) is involved in the epigenetic regulation of genes by targeting DNA methyltransferases ( DNMT ), which methylate CpG islands to suppress the transcription of genes. We studied the involvement of miR ‐29a in TGF ‐β‐induced EMT in HCC cells. Methods We treated human HCC cell lines with TGF ‐β to induce EMT . To investigate DNA methylation in EMT , cells were treated with a methylation inhibitor, 5‐ A za‐2′‐deoxycytidine (5‐ Aza ) and methylation status of CpG islands in the E ‐cadherin promoter was examined using methylation‐specific PCR . Precursor miR ‐29a (pre‐ miR ‐29a) was electroporated to force the expression of miR ‐29a in HCC cells in order to study the role of miR ‐29a in EMT . Results TGF ‐β transformed HCC cells into a spindle‐shaped morphology accompanied by a decrease of E ‐cadherin with the induction of methylation of its promoter. Pretreatment of the cells with 5‐ Aza blocked this suppression of E ‐cadherin, indicating the involvement of DNA methylation. TGF ‐β increased DNMT3B and DNMT1 and decreased miR ‐29a expression. The forced expression of miR ‐29a abrogated the suppression of E ‐cadherin induced by TGF ‐β. Conclusion miR ‐29a could regulate TGF ‐β‐induced EMT by affecting DNA methylation via the suppression of DNMT . These observations reveal the epigenetic regulation of genes by mi RNA as a unique mechanism of EMT in HCC .