miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer
miR-152 Is a Tumor Suppressor microRNA That Is Silenced by DNA Hypermethylation in Endometrial Cancer
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DOI：
10.1158/0008-5472.can-11-0364
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发表时间：
2011-10-15
期刊：
影响因子：
11.2
通讯作者：
Inazawa, Johji
中科院分区：
文献类型：
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作者：
Tsuruta, Tomohiko;Kozaki, Ken-ichi;Inazawa, Johji
肿瘤抑制microrna （TS-miRNA）的定义可能会启发我们对人类癌症的病因和发展知之甚少。在这项研究中，我们在子宫内膜癌中发现了被异常DNA高甲基化沉默的TS-miRNAs。在子宫内膜癌细胞增殖试验中对327种合成mirna进行功能筛选，鉴定出103种抑制细胞生长的mirna。然后，我们确定了这些mirna在子宫内膜癌细胞系和原发性肿瘤中的序列、DNA甲基化状态和表达水平。这些确定导致miR-152被鉴定为子宫内膜癌的候选TS-miRNA基因。miR-152中记录的表观遗传沉默与其位于COPZ2基因内含子1 17q21.32的位置一致，COPZ2基因在子宫内膜癌中也经常因DNA高甲基化而沉默，并且也有证据表明miR-152靶向DNA甲基转移酶DNMT1。值得注意的是，恢复miR-152在子宫内膜癌细胞系中的表达足以在体外和体内抑制肿瘤细胞的生长。我们确定了E2F3、MET和Rictor作为miR-152的新候选靶点，提示其表观遗传沉默如何驱动子宫内膜癌的发生。我们的研究结果确定了miR-152在子宫内膜癌中的核心作用，并建议将其用于治疗这种癌症的新治疗策略。癌症Res;71 (20);6450 - 62。(c) 2011年aacr。
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. Functional screening of 327 synthetic miRNAs in an endometrial cancer 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 endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. 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 endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer 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 epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Cancer Res; 71(20); 6450-62. (C) 2011 AACR.