Dong Peixin, Ihira Kei, Xiong Ying, Watari Hidemichi, Hanley Sharon J B, Yamada Takahiro, Hosaka Masayoshi, Kudo Masataka, Yue Junming, Sakuragi Noriaki
Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
Oncotarget. 2016 Apr 12;7(15):20260-70. doi: 10.18632/oncotarget.7754.
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.
IQGAP1的过表达和微小RNA（miRNA）失调在人类肿瘤中很常见，但关于IQGAP1在子宫内膜癌发生中的作用及其与miRNA的关系却知之甚少。我们证明IQGAP1激活上皮-间质转化（EMT）程序，并且miR-124在子宫内膜癌（EC）细胞中直接抑制IQGAP1的表达。IQGAP1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IQGAP1表达则逆转EMT并抑制这些恶性特性。通过miRNA微阵列分析，我们鉴定出29种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-409-3p、miR-422b、miR-424、miR-453、miR-497、miR-518d、miR-518f*、miR-526a和miR-656），相对于亲代HEC-50细胞，这些miRNA在体外筛选的高侵袭性衍生细胞系（HEC-50-HI）中显著下调。我们进一步鉴定出miR-124是EC细胞中IQGAP1的直接调节因子。miR-124的强制表达抑制EC细胞的侵袭和增殖。IQGAP1 mRNA在EC组织中的表达显著升高，而miR-124的表达则降低。miR-124的下调与EC患者的不良生存结果相关。用去甲基化剂5-氮杂-2'-脱氧胞苷处理EC细胞可增加miR-124的表达并下调IQGAP1水平。我们的数据表明IQGAP1促进EC细胞的EMT以及迁移和侵袭。miR-124是一种新型肿瘤抑制性miRNA，在EC中通过表观遗传沉默，它可以通过减弱IQGAP1癌基因的表达来逆转EMT和侵袭特性。
