A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer
A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer
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DOI：
10.1210/me.2009-0295
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发表时间：
2010-02-01
影响因子：
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通讯作者：
Matzuk, Martin M.
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作者：
Nagaraja, Ankur K.;Creighton, Chad J.;Matzuk, Martin M.
microRNAs（miRNAs）是一类小的非编码RNA，通过翻译抑制和降解互补mRNA来指导基因调控。尽管miRNA在多种人类癌症中被认为是致癌基因和肿瘤抑制因子，但单个miRNA在卵巢透明细胞癌（卵巢癌的侵袭性和化疗耐药亚型）中的功能作用尚未被描述。我们进行了深度测序，以全面分析10种人透明细胞卵巢癌细胞系与正常卵巢表面上皮培养物相比的miRNA表达，并发现了54种异常表达的miRNA。由于磷脂酰肌醇3-激酶/v-akt小鼠胸腺瘤病毒癌基因同源物1/哺乳动物雷帕霉素靶蛋白（mTOR）通路在透明细胞卵巢癌中的关键作用，我们将重点放在mir-100（一种假定的肿瘤抑制因子，在我们的癌细胞系中是下调最多的miRNA）及其上调靶蛋白FRAP 1/mTOR上。mir-100的过表达抑制mTOR信号传导并增强对雷帕霉素类似物RAD001（依维莫司）的敏感性，证实了mir-100和mTOR通路之间的关键关系。此外，假定的肿瘤抑制因子mir-22的过表达抑制了EVI1癌基因，已知EVI1癌基因通过刺激磷脂酰肌醇3-激酶/v-akt鼠胸腺瘤病毒癌基因同源物1信号传导来抑制细胞凋亡。除了这些特定的影响，逆转mir-22和假定的致癌基因mir-182的表达对靶基因和非靶基因群体具有广泛的影响，最终导致癌症基因特征向更正常状态的全球转变。我们的实验揭示了可能有助于透明细胞卵巢癌发病机制的强候选miRNAs及其靶基因，从而突出了治疗这种致命癌症的替代治疗策略。（分子内分泌学24：447 - 463，2010）
MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer. (Molecular Endocrinology 24: 447-463, 2010)