MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells.

Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE

Original Publication: Oxford, UK : Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies, c2005-

Carcinoma/*genetics ; Hyaluronan Receptors/*genetics ; MicroRNAs/*genetics ; Neoplastic Stem Cells/*metabolism ; Ovarian Neoplasms/*genetics; 3' Untranslated Regions/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Adult ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/biosynthesis ; Biomarkers, Tumor/genetics ; Carcinoma/drug therapy ; Carcinoma/pathology ; Cell Cycle ; Cell Movement ; Cell Proliferation ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Genes, Reporter ; Humans ; Hyaluronan Receptors/metabolism ; Luciferases/genetics ; Mice ; MicroRNAs/metabolism ; Middle Aged ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplastic Stem Cells/pathology ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Xenograft Model Antitumor Assays

In ovarian cancer, CD44(+) /CD117(+) stem cells, also known as cancer-initiating cells (CICs), are highly proliferative, have a low degree of differentiation, and are resistant to chemotherapeutics. Therefore, the CD44(+) /CD117(+) subpopulation is thought to be an important target for novel therapeutic strategies. In this study, we investigated the role of microRNA-199a (miR-199a) in ovarian cancer stem cells. Luciferase reporter gene assays confirmed that miR-199a targets CD44 via an miR-199a-binding site in the 3'-UTR. CD44(+) /CD117(+) ovarian CICs were enriched from human primary ovarian tumor tissues and confirmed by flow cytometric sorting. miR-199a was cloned and transfected into ovarian CICs. CD44 mRNA and protein expression was significantly decreased in miR-199a-transfected ovarian CICs as compared with miR-199a mutant-transfected and untransfected cells. Cell cycle analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide proliferation assays, the colony formation assay and the transwell migration assay indicated that miR-199a significantly affected cell cycle regulation and suppressed the proliferation and invasive capacity of ovarian CICs in vitro. miR-199a significantly increased the chemosensitivity of ovarian CICs to cisplatin, pacitaxel, and adriamycin, and reduced mRNA expression of the multidrug resistance gene ABCG2 as compared with miR-199a mutant-transfected and untransfected cells. The expression of stemness markers was also significantly reduced in miR-199a-transfected CICs as compared with miR-199a mutant-transfected and untransfected ovarian cells. Furthermore, xenograft experiments confirmed that miR-199a suppressed the growth of xenograft tumors formed by ovarian CICs in vivo. Thus, expression of endogenous mature miR-199a may prevent tumorigenesis in human ovarian cancer by regulating expression of its target gene CD44.
(© 2012 The Authors Journal compilation © 2012 FEBS.)

0 (3' Untranslated Regions)
0 (ABCG2 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (ATP-Binding Cassette Transporters)
0 (Antineoplastic Agents)
0 (Biomarkers, Tumor)
0 (Hyaluronan Receptors)
0 (MicroRNAs)
0 (Neoplasm Proteins)
0 (mirn199 microRNA, human)
EC 1.13.12.- (Luciferases)

Date Created: 20120414 Date Completed: 20120705 Latest Revision: 20220719

20221213

10.1111/j.1742-4658.2012.08589.x

22498306