Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

Abstract

A number of microRNAs (miRNAs), including miR-200 family, are aberrantly expressed in endometriosis and endometrial cancer. Here we assessed the expression and functional aspects of miR-200c in endometrial tissues (N ¼ 52) from normal endometrial biopsies (N ¼ 15), endometrial tissues including those exposed to hormonal therapies (N ¼ 20), and grade I-III endometrial cancer (N ¼ 17). miR-200c expression was elevated in normal endometrial biopsies from mid-and late-luteal phase, and in endometrial tumors as compared to endometrial tissues from peri-and postmenopausal period (P < .05) and its pattern of temporal expression displayed an inverse relationship with the expression of ZEBs. 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 proliferative phase; however, treatment of Ishikawa cells with 17b-estradiol, progesterone, and medroxy progesterone acetate had modest 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 3 0 untranslated regions and increased the rate of their proliferation. These results indicated that endometrial miR200c 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.

Integrated MicroRNA Network Analyses Identify a Poor-Prognosis Subtype of Gastric Cancer Characterized by the miR-200 Family

“…We cannot absolutely rule out chance findings in this study, although there are several studies indicating that the miR-200 family may be related to hormones (35,36). Gastric cancer is a hormone-related cancer.…”

Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis1

“…Its relevance to the pathology of uterine diseases has been supported in another mouse model [17] and more importantly in women, wherein loss of its endometrial and myometrial expression was associated with endometrial cancer, endometriosis, myoma and prolonged labor [18][19][20][21][22]. To investigate a causal relationship between endometriosis and loss of KLF9, we recently developed a mouse model using a syngeneic immunocompetent mouse as recipient of donor endometria from Klf9 null and corresponding wild-type mice [23].…”

MicroRNAs, immune cells and pregnancy

“…116 The most widely studied pro-angiogenic factor is VEGF, and miRNA-mediated control over angiogenesis, specifically by modulating VEGF transcripts, has been demonstrated. [117][118][119][120][121] While there are many pro-and anti-angiogenic miRNAs, each member of the miRNA-17-92 cluster (miR-17, -18a, -19a, -19b, -20a and -92a), has been shown to have anti-angiogenic effects on endothelial cell sprouting in vitro and inhibition of these miRNAs increased endothelial sprouting. 122 This effect can also be seen in vivo in a mouse lung cancer model where systemic blockade of the miR-17-92 cluster promoted tumor neovascularization.…”