MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in hepatocellular carcinogenesis.
In general, microRNAs, a class of small (~21 nucleotide) non-coding RNAs, negatively regulate the expression of their target genes. Dysregulation of miRNAs is a common feature in human cancers, but this phenomenon has not been studied extensively in hepatocellular carcinoma (HCC). miR‑148a, a member of the miR-148/152 family, has been found to be downregulated in several tumor types and has been suggested to be a tumor suppressor gene; however, its function in HCC remains unclear. Herein, we describe the epigenetic regulation of miR-148a and its impact on HCC cells. We found that, due to the hypermethylation of its CpG island, miR-148a undergoes methylation-mediated silencing in HCC cell lines. Additionally, DNMT1, the DNA methyltransferase that maintains methylation patterns, is aberrantly upregulated in HCC cell lines, and its overexpression is responsible for hypermethylation of the miR-148a promoter. Intriguingly, the expression of DNMT1, which is a target of miR-148a, is inversely correlated with the expression of miR-148a in HCC cells. These results lead us to propose the existence of a negative feedback regulatory loop between miR-148a and DNMT1 in HCC. Importantly, we demonstrate that the overexpression of miR-148a significantly inhibits HCC cell proliferation and cell cycle progression. Our results suggest the existence of a novel miR-148a-DNMT1 regulatory circuit and indicate that miR-148a acts as a tumor suppressor during hepatocellular carcinogenesis. These results may provide a promising alterative strategy for the therapeutic treatment of HCC.
School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, P.R. China.
Xiao-Ran
XR
Long
School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, P.R. China.
Yong
Y
He
School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, P.R. China.
Cheng
C
Huang
School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, P.R. China.
Jun
J
Li
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic
D004791:Enzyme Inhibitors; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D001374:Azacitidine