Frequent downregulation of miR-34 family in human ovarian cancers

David C. Corney, Chang Il Hwang, Andres Matoso, Markus Vogt, Andrea Flesken-Nikitin, Andrew K. Godwin, Aparna A. Kamat, Anil K. Sood, Lora H. Ellenson, Heiko Hermeking, Alexander Yu Nikitin

Research output: Contribution to journalArticle

247 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1119-1128
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number4
DOIs
StatePublished - Feb 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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