Original Articles Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs,

A number of microRNAs (miRNAs), including miR-200 family, are aberrantly expressed in endometriosis and endometrial cancer. Hereweassessed theexpression and functional aspectsofmiR-200c inendometrial tissues (N 52) fromnormal endometrial biopsies (N 15), endometrial tissues including those exposed to hormonal therapies (N 20), and grade I-III endometrial cancer (N 17). miR-200c expressionwas elevated in normal endometrial biopsies frommid- and late-luteal phase, and in endometrial tumors as com-pared to endometrial tissues from peri- and postmenopausal period (P <.05) and its pattern of temporal expression displayed an inverse relationship with the expression ofZEBs. The expression of E-cadherin (CDH1) varied, but expressed at low levels, specifically in endometrial tissues and endometrial tumors. The endometrial expression of ZEBs and CDH1 in patients who were exposed to Depo-Provera and gonadotropin-releasing hormone agonist GnRHa displayed a trend toward lower expression as compared to pro-liferative phase; however, treatment of Ishikawa cells with 17b-estradiol, progesterone, andmedroxy progesterone acetate hadmod-est effects on the expression of miR-200c and ZEBs without affecting CDH1 expression. Gain of function of miR-200c in Ishikawa cells repressed ZEBs, as well as VEGFA, FLT1, IKKb, and KLF9 expression at transcriptional and translational levels through direct interaction with their respective 30untranslated regions and increased the rate of their proliferation. These results indicated that endometrialmiR-200c expression undergoes dynamic changes during transition from normal into cancerous states; possibly influenced by hormonal milieu and by targeting the expression of specific genes with key regulatory functions in cellular transformation, inflammation, and angiogenesis may influence these events during normal and disease progression.