title: Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.
abstract: MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.
authors.forename: T K H
authors.initials: TK
authors.lastname: Chung
authors.forename: T S
authors.initials: TS
authors.lastname: Lau
authors.forename: T H
authors.initials: TH
authors.lastname: Cheung
authors.forename: S F
authors.initials: SF
authors.lastname: Yim
authors.forename: K W K
authors.initials: KW
authors.lastname: Lo
authors.forename: N S S
authors.initials: NS
authors.lastname: Siu
authors.forename: L K Y
authors.initials: LK
authors.lastname: Chan
authors.forename: M Y
authors.initials: MY
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Kwong
authors.forename: G
authors.initials: G
authors.lastname: Doran
authors.forename: L M
authors.initials: LM
authors.lastname: Barroilhet
authors.forename: A S W
authors.initials: AS
authors.lastname: Ng
authors.forename: R R Y
authors.initials: RR
authors.lastname: Wong
authors.forename: V W
authors.initials: VW
authors.lastname: Wang
authors.forename: S C
authors.initials: SC
authors.lastname: Mok
authors.forename: D I
authors.initials: DI
authors.lastname: Smith
authors.forename: R S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Y F
authors.initials: YF
authors.lastname: Wong
mesh_terms: D020413:3' Untranslated Regions; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D016889:Endometrial Neoplasms; D004717:Endometrium / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D014162:Transfection; D054928:Validation Studies as Topic
chemical_list: D020413:3' Untranslated Regions; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C549404:MIRN204 microRNA, human; D035683:MicroRNAs