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 Hawkins, Martin M. Matzuk

Research output: Contribution to journalArticle

9 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Ovarian Neoplasms
MicroRNAs
Fallopian Tubes
Neoplasms
Carcinoma
Knockout Mice
Carcinogenesis
G1 Phase
Cell Cycle Checkpoints
Tumor Cell Line
Cell Survival
Cell Cycle
Adenocarcinoma
Cell Proliferation
Apoptosis
Cell Line
Genes

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer. / Yu, Zhifeng; Kim, Jaeyeon; He, Lin; Creighton, Chad J.; Gunaratne, Preethi H.; Hawkins, Shannon; Matzuk, Martin M.

In: Biology of Reproduction, Vol. 91, No. 5, 113, 01.11.2014.

Research output: Contribution to journalArticle

Yu, Zhifeng ; Kim, Jaeyeon ; He, Lin ; Creighton, Chad J. ; Gunaratne, Preethi H. ; Hawkins, Shannon ; Matzuk, Martin M. / Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer. In: Biology of Reproduction. 2014 ; Vol. 91, No. 5.
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