Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression.
Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression.
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DOI：
10.18632/oncotarget.7754
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发表时间：
2016-04-12
期刊：
影响因子：
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通讯作者：
Sakuragi N
中科院分区：
文献类型：
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作者：
Dong P;Ihira K;Xiong Y;Watari H;Hanley SJ;Yamada T;Hosaka M;Kudo M;Yue J;Sakuragi N
IQGAP 1的过度表达和microRNA（miRNA）的失调在人类肿瘤中是常见的，但关于IQGAP 1的作用及其与miRNA在子宫内膜癌发生中的关系知之甚少。我们证明IQGAP 1激活上皮-间质转化（EMT）程序，miR-124直接抑制IQGAP 1在子宫内膜癌（EC）细胞中的表达。IQGAP 1的过表达刺激EMT特征并增强EC细胞的迁移、侵袭和增殖，而敲低IQGAP 1表达逆转EMT并抑制这些恶性性质。使用miRNA微阵列分析，我们鉴定了29个miRNA，（let-7b，let-7f，miR-10b，miR-15b，miR-23a，miR-24，miR-25，miR-27a，miR-29b，miR-30a-5p，miR-34a，miR-124，miR-127，miR-130b，miR-148a，miR-155，miR-191*，miR-194，miR-224，miR-362，miR-409- 3 p、miR-422 b、miR-424、miR-453、miR-497、miR-518 d、miR-518 f *、miR-526 a和miR-656），其在体外选择的高度侵袭性衍生细胞系（HEC-50-HI）中相对于亲本HEC-50细胞显著下调。我们进一步鉴定了miR-124作为EC细胞中IQGAP 1的直接调节因子。miR-124的增强表达抑制EC细胞侵袭和增殖。食管癌组织中IQGAP 1 mRNA表达显著升高，而miR-124表达显著降低。miR-124的下调与EC患者的不良生存结局相关。用去甲基化剂5-氮杂-2 ′-脱氧胞苷处理EC细胞增加miR-124表达并下调IQGAP 1水平。我们的数据表明IQGAP 1促进EC细胞的EMT、迁移和侵袭。MiR-124是一种在EC中表观遗传学沉默的新型肿瘤抑制miRNA，可以通过减弱IQGAP 1癌基因的表达来逆转EMT和侵袭性。
Overexpression of IQGAP1 and microRNA (miRNA) dysregulation are frequent in human tumors, but little is known about the role of IQGAP1 and its relationship to miRNA in endometrial carcinogenesis. We demonstrate that IQGAP1 activates the epithelial–mesenchymal transition (EMT) program and that miR-124 directly represses IQGAP1 expression in endometrial cancer (EC) cells. The overexpression of IQGAP1 stimulates EMT features and enhances migration, invasion and proliferation of EC cells, whereas knocking down IQGAP1 expression reverses EMT and inhibits these malignant properties. Using miRNA microarray profiling, we identified 29 miRNAs (let-7b, let-7f, miR-10b, miR-15b, miR-23a, miR-24, miR-25, miR-27a, miR-29b, miR-30a-5p, miR-34a, miR-124, miR-127, miR-130b, miR-148a, miR-155, miR-191*, miR-194, miR-224, miR-362, miR-409-3p, miR-422b, miR-424, miR-453, miR-497, miR-518d, miR-518f*, miR-526a and miR-656) that are significantly down-regulated in an in vitro-selected highly invasive derivative cell line (HEC-50-HI) relative to the parental HEC-50 cells. We further identified miR-124 as a direct regulator of IQGAP1 in EC cells. Enforced expression of miR-124 suppresses EC cell invasion and proliferation. The expression of IQGAP1 mRNA was significantly elevated in EC tissues, while the expression of miR-124 was decreased. The downregulation of miR-124 correlates with a poor survival outcome for patients with EC. Treating EC cells with the demethylating agent 5-aza-2′-deoxycytidine increased miR-124 expression and down-regulated IQGAP1 levels. Our data suggest that IQGAP1 promotes EMT, migration and invasion of EC cells. MiR-124, a novel tumor suppressor miRNA that is epigenetically silenced in EC, can reverse EMT and the invasive properties, by attenuating the expression of the IQGAP1 oncogene.