title: 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.
abstract: 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.
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Peixin
authors.initials: P
authors.lastname: Dong
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ihira
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Watari
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Sharon J B
authors.initials: SJ
authors.lastname: Hanley
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Hosaka
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Sapporo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, TN, USA.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: 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.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakuragi
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D057890:Epigenomics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C101203:IQ motif containing GTPase activating protein 1; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D020703:ras GTPase-Activating Proteins
keywords: DNA methyltransferase inhibitor; IQGAP1; endometrial cancer cell invasion; epigenetics; miR-124