Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET

T. Mitamura, H. Watari, L. Wang, H. Kanno, M. K. Hassan, M. Miyazaki, Y. Katoh, T. Kimura, M. Tanino, Hiroshi Nishihara, S. Tanaka, N. Sakuragi

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Abstract

Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3′-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy.

Original languageEnglish
Article numbere40
JournalOncogenesis
Volume2
DOIs
Publication statusPublished - 2013 Jul 29
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-met
Paclitaxel
MicroRNAs
Ovarian Neoplasms
Down-Regulation
taxane
3' Untranslated Regions
Neoplasms
Cell Line
Messenger RNA

Keywords

  • chemoresistance
  • MET
  • microRNA
  • ovarian cancer
  • paclitaxel

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. / Mitamura, T.; Watari, H.; Wang, L.; Kanno, H.; Hassan, M. K.; Miyazaki, M.; Katoh, Y.; Kimura, T.; Tanino, M.; Nishihara, Hiroshi; Tanaka, S.; Sakuragi, N.

In: Oncogenesis, Vol. 2, e40, 29.07.2013.

Research output: Contribution to journalArticle

Mitamura, T, Watari, H, Wang, L, Kanno, H, Hassan, MK, Miyazaki, M, Katoh, Y, Kimura, T, Tanino, M, Nishihara, H, Tanaka, S & Sakuragi, N 2013, 'Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET', Oncogenesis, vol. 2, e40. https://doi.org/10.1038/oncsis.2013.3
Mitamura, T. ; Watari, H. ; Wang, L. ; Kanno, H. ; Hassan, M. K. ; Miyazaki, M. ; Katoh, Y. ; Kimura, T. ; Tanino, M. ; Nishihara, Hiroshi ; Tanaka, S. ; Sakuragi, N. / Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. In: Oncogenesis. 2013 ; Vol. 2.
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