title: MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1.
abstract: MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3' untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC.
authors.affiliation: Department of Gynecology, The Second Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Yan-Ying
authors.initials: YY
authors.lastname: Xu
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Wu
authors.forename: Hong-Da
authors.initials: HD
authors.lastname: Ma
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Huo
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yin
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000818:Animals; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004714:Endometrial Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C530104:CCND1 protein, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D011994:Recombinant Proteins; D019938:Cyclin D1
keywords: cyclin D1; endometrioid endometrial cancer; miR-503; microRNA; target gene