title: Tamoxifen represses miR-200 microRNAs and promotes epithelial-to-mesenchymal transition by up-regulating c-Myc in endometrial carcinoma cell lines.
abstract: Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jiu-Xu
authors.initials: JX
authors.lastname: Bai
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.forename: Zhi-Ning
authors.initials: ZN
authors.lastname: Zhao
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Qin
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Meng
authors.forename: Bo-Quan
authors.initials: BQ
authors.lastname: Jin
authors.forename: Dai-Ming
authors.initials: DM
authors.lastname: Fan
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000139:chemically induced*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen