title: Loss of miR-200c: A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers.
abstract: We focus on unique roles of miR-200c in breast, ovarian, and endometrial cancers. Members of the miR-200 family target ZEB1, a transcription factor which represses E-cadherin and other genes involved in polarity. We demonstrate that the double negative feedback loop between miR-200c and ZEB1 is functional in some, but not all cell lines. Restoration of miR-200c to aggressive cancer cells causes a decrease in migration and invasion. These effects are independent of E-cadherin status. Additionally, we observe that restoration of miR-200c to ovarian cancer cells causes a decrease in adhesion to laminin. We have previously reported that reintroduction of miR-200c to aggressive cells that lack miR-200c expression restores sensitivity to paclitaxel. We now prove that this ability is a result of direct targeting of class III beta-tubulin (TUBB3). Introduction of a TUBB3 expression construct lacking the miR-200c target site into cells transfected with miR-200c mimic results in no change in sensitivity to paclitaxel. Lastly, we observe a decrease in proliferation in cells transfected with miR-200c mimic, and cells where ZEB1 is knocked down stably, demonstrating that the ability of miR-200c to enhance sensitivity to paclitaxel is not due to an increased proliferation rate.
authors.affiliation: Department of Pathology, Denver School of Medicine, University of Colorado, Aurora CO, 80045, USA.
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Cochrane
authors.forename: Erin N
authors.initials: EN
authors.lastname: Howe
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Spoelstra
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer