Involvement of miRNA-29a in epigenetic regulation of transforming growth factor-β-induced epithelial-mesenchymal transition in hepatocellular carcinoma

被引：34

作者：

Kogure, Takayuki ^{[1
]}

Kondo, Yasuteru ^{[1
]}

Kakazu, Eiji ^{[1
]}

Ninomiya, Masashi ^{[1
]}

Kimura, Osamu ^{[1
]}

Shimosegawa, Tooru ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Miyagi 980, Japan

来源：

HEPATOLOGY RESEARCH | 2014年 / 44卷 / 08期

基金：

日本学术振兴会;

关键词：

E-cadherin; epithelial-mesenchymal transition; hepatocellular carcinoma; miR-29a; TRANSCRIPTION FACTOR SNAIL; E-CADHERIN; DNA METHYLATION; TGF-BETA; TUMOR-SUPPRESSOR; GENE-EXPRESSION; MICRORNA-29; CANCER; METASTASIS; PROGNOSIS;

D O I：

10.1111/hepr.12188

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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)-beta. Recent studies have shown that the epigenetic regulation of E-cadherin could be an alternate mechanism of EMT induction in hepatocellular carcinoma (HCC). miRNA-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-beta-induced EMT in HCC cells. Methods: We treated human HCC cell lines with TGF-beta to induce EMT. To investigate DNA methylation in EMT, cells were treated with a methylation inhibitor, 5-Aza-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-beta 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-beta increased DNMT3B and DNMT1 and decreased miR-29a expression. The forced expression of miR-29a abrogated the suppression of E-cadherin induced by TGF-beta. Conclusion: miR-29a could regulate TGF-beta-induced EMT by affecting DNA methylation via the suppression of DNMT. These observations reveal the epigenetic regulation of genes by miRNA as a unique mechanism of EMT in HCC.

引用

页码：907 / 919

页数：13

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