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Corney DC , Hwang CI , Matoso A , Vogt M , Flesken-Nikitin A , Godwin AK , Kamat AA , Sood AK , Ellenson LH , Hermeking H , Nikitin AY
Frequent Downregulation of miR-34 Family in Human Ovarian Cancers
Clinical Cancer Research. 2010 Feb;16(4) :1119-1128
PMID: ISI:000278545200006   
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Purpose: The miR-34 family is directly transactivated by tumor suppressor p53, which is frequently mutated in human epithelial ovarian cancer (EOC). We hypothesized that miR-34 expression would be decreased in EOC and that reconstituted miR-34 expression might reduce cell proliferation and invasion of EOC cells. Experimental Designs: miR-34 expression was determined by quantitative reverse transcription-PCR and in situ hybridization in a panel of 83 human EOC samples. Functional characterization of miR-34 was accomplished by reconstitution of miR-34 expression in EOC cells with synthetic pre-miR molecules followed by determining changes in proliferation, apoptosis, and invasion. Results: miR-34a expression is decreased in 100%, and miR-34b*/c in 72%, of EOC with p53 mutation, whereas miR-34a is also downregulated in 93% of tumors with wild-type p53. Furthermore, expression of miR-34b*/c is significantly reduced in stage IV tumors compared with stage III (P = 0.0171 and P = 0.0029, respectively). Additionally, we observed promoter methylation and copy number variations at mir-34. In situ hybridization showed that miR-34a expression is inversely correlated with MET immunohistochemical staining, consistent with translational inhibition by miR-34a. Finally, miR-34 reconstitution experiments in p53 mutant EOC cells resulted in reduced proliferation, motility, and invasion, the latter of which was dependent on MET expression. Conclusions: Our work suggests that miR-34 family plays an important role in EOC pathogenesis and reduced expression of miR-34b*/c may be particularly important for progression to the most advanced stages. Part of miR-34 effects on motility and invasion may be explained by regulation of MET, which is frequently overexpressed in EOC. Clin Cancer Res; 16(4); 1119-28. (C) 2010 AACR.
Corney, David C. Hwang, Chang-Il Matoso, Andres Vogt, Markus Flesken-Nikitin, Andrea Godwin, Andrew K. Kamat, Aparna A. Sood, Anil K. Ellenson, Lora H. Hermeking, Heiko Nikitin, Alexander Yu. NIH [CA112354, RR17595]; Marsha Rivkin Cancer Center Pilot Study ; Cornell Vertebrate Genomics Scholarship ; College of Veterinary Medicine ; Ovarian Cancer Research [CUMC/POE02.06]; University of Texas M.D. Anderson Cancer Center [P50 CA083639]; Ovarian Cancer Research Fund, Inc. Grant Support NIH grants CA112354 and RR17595 and Marsha Rivkin Cancer Center Pilot Study (A.Y. Nikitin), Cornell Vertebrate Genomics Scholarship (D.C. Corney), Graduate Research Assistantship of the College of Veterinary Medicine (C.-I. Hwang), Ovarian Cancer Research Fund Program of Excellence in Ovarian Cancer Research Postdoctoral Fellowship grant CUMC/POE02.06 (A. Matoso), and University of Texas M.D. Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence grant P50 CA083639 and Ovarian Cancer Research Fund, Inc. (A.K. Sood). 47 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 607zg