Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer

Zhifeng Yu, Jaeyeon Kim, Lin He, Chad J. Creighton, Preethi H. Gunaratne, Shannon M. Hawkins, Martin M. Matzuk

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Abstract

Altered microRNA expression patterns are implicated in the formation of many human diseases, including ovarian cancer. Our laboratory previously created Dicerfl/fl/Ptenfl/fl/Amhr2cre/+ mice, which developed high-grade serous carcinomas originating from mouse fallopian tubes, while neither Dicerfl/fl/Amhr2cre/+ nor Ptenfl/fl/Amhr2cre/+ mice developed tumors. To explore miRNAs involved in the tumorigenesis in the double-knockout (DKO) mice, tumor cell lines were established from mouse primary tumors, and the most abundant miRNAs present in mouse normal fallopian tubes, let-7b and miR-34c, were expressed in these cell lines. We found that miR-34c had a more dramatic effect on inhibiting tumor cell viability than let-7b. The action of miR-34c induced tumor cell cycle arrest in G1 phase and apoptosis, and was accompanied with the regulation of key genes involved in cell proliferation and cell cycle G1/S transition. miR-34c suppressed the expression of Ezh2 and Mybl2, which may transcriptionally and functionally activate Cdkn1c. Furthermore, miR-34c levels are extremely low in human serous adenocarcinomas compared with human normal fallopian tubes. Expression of miR-34c in human ovarian cancer cells phenocopied its effects in DKO mouse tumor cells. However, miR-34b/c-/-/Ptenfl/fl/Amhr2cre/+ mice failed to develop high-grade serous carcinomas, implicating a combination of miRNAs in the tumorigenesis process. Thus, while miR-34c is a putative tumor suppressor in high-grade serous ovarian carcinoma with potential therapeutic advantages, screening of additional miRNAs for their effects alone and in combination with miR-34c is highly warranted to uncover miRNAs that synergize with miR-34c against cancer.

Original languageEnglish (US)
Article number113
JournalBiology of Reproduction
Volume91
Issue number5
DOIs
StatePublished - Nov 1 2014

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Keywords

  • Dicer/Pten double knockout
  • Ovarian cancer
  • miR-34b/c/Pten double knockout
  • microRNA

ASJC Scopus subject areas

  • Reproductive Medicine
  • Cell Biology

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