miR-152は子宮体癌においてDNA過剰メチル化により発現抑制される癌抑制遺伝子型microRNAである(優秀論文賞受賞講演,第64回日本産科婦人科学会・学術講演会)

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The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer (EC). Functional screening of 327 synthetic miRNAs in an EC cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in EC cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in EC. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in EC by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in EC cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetically silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in EC, and they also suggest its use in new therapeutic strategies to treat this cancer.
2012-08-01