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.

Peixin Dong, Kei Ihira, Ying Xiong, Hidemichi Watari, Sharon J. B. Hanley, Takahiro Yamada, Masayoshi Hosaka, Masataka Kudo, Junming Yue, Noriaki Sakuragi

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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.
Original languageEnglish
Pages (from-to)20260-20270
Number of pages11
Issue number15
Early online date26 Feb 2016
Publication statusPublished - 26 Feb 2016

Bibliographical note

We thank Professor Kozo Kaibuchi for providing plasmids (pEGFR-IQGAP1-WT and pEGFR empty vector) and Dr. Zhujie Xu for technical assistance. The authors wish to thank Dr. Victor Manuel Treviño Alvarado (Tecnológico de Monterrey, Campus Monterrey) for his constructive comments.
The authors declare no conflicts of interest.
This work was funded by a grant from the Department of Women’s Health Educational System, a Grant-in-Aid for Scientific Research (C) (15K10697) and Science and Technology Planning Project of Guangdong Province, China (2013B021800155).


  • Female
  • Humans
  • Neoplasm Invasiveness
  • MicroRNAs/*genetics
  • Tumor Cells, Cultured
  • Cell Movement
  • Cell Proliferation
  • Prognosis
  • *Epigenomics
  • *Gene Expression Regulation, Neoplastic
  • Apoptosis
  • Biomarkers, Tumor/genetics
  • DNA Methylation
  • DNA methyltransferase inhibitor
  • endometrial cancer cell invasion
  • Endometrial Neoplasms/*genetics/*pathology
  • epigenetics
  • Epithelial-Mesenchymal Transition
  • IQGAP1
  • miR-124
  • ras GTPase-Activating Proteins/genetics/*metabolism
  • Survival Rate


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