title: Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET.
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.
authors.affiliation: 1] Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan [2] Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mitamura
authors.forename: H
authors.initials: H
authors.lastname: Watari
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Kanno
authors.forename: M K
authors.initials: MK
authors.lastname: Hassan
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Katoh
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: M
authors.initials: M
authors.lastname: Tanino
authors.forename: H
authors.initials: H
authors.lastname: Nishihara
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Sakuragi
references.citation: Lancet. 1997 Jan 11;349(9045):113-7
references.pmid: 8996432
references.citation: Mol Cell. 2002 May;9(5):993-1004
references.pmid: 12049736
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references.pmid: 16461460
references.citation: Cancer Res. 2010 Mar 1;70(5):1906-15
references.pmid: 20179198
references.citation: Nat Rev Mol Cell Biol. 2010 Dec;11(12):834-48
references.pmid: 21102609
references.citation: Cancer Sci. 2009 Mar;100(3):546-51
references.pmid: 19154404
references.citation: Neoplasia. 2010 Feb;12(2):128-38
references.pmid: 20126471
references.citation: Nat Rev Cancer. 2011 Sep 23;11(10):719-25
references.pmid: 21941283
references.citation: Cancer Res. 2007 Feb 15;67(4):1670-9
references.pmid: 17308108
references.citation: Cancer Res. 2010 Jun 15;70(12):5184-93
references.pmid: 20501828
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references.pmid: 12434020
references.citation: N Engl J Med. 2004 Dec 9;351(24):2519-29
references.pmid: 15590954
references.citation: Clin Cancer Res. 2010 Nov 15;16(22):5489-98
references.pmid: 21062933
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21098-103
references.pmid: 21078976
references.citation: Nat Rev Drug Discov. 2010 Oct;9(10):775-89
references.pmid: 20885409
references.citation: Eur J Cancer. 2009 Jan;45(2):228-47
references.pmid: 19097774
references.citation: J Biol Chem. 2008 Oct 31;283(44):29897-903
references.pmid: 18708351
references.citation: CA Cancer J Clin. 1999 Jan-Feb;49(1):8-31, 1
references.pmid: 10200775
references.citation: N Engl J Med. 1995 Mar 9;332(10):629-34
references.pmid: 7845426
references.citation: J Biol Chem. 2010 Jul 23;285(30):22809-17
references.pmid: 20463022
references.citation: Curr Opin Genet Dev. 1996 Oct;6(5):610-7
references.pmid: 8939727
references.citation: Cancer Genomics Proteomics. 2006 Oct;3(5):317-324
references.pmid: 18172508
references.citation: Nat Med. 1996 Jan;2(1):72-9
references.pmid: 8564846
references.citation: J Natl Cancer Inst. 1986 Dec;77(6):1181-5
references.pmid: 3467111
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2503-8
references.pmid: 20133800
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1326-34
references.pmid: 19228734
references.citation: Cancer Res. 2010 Dec 1;70(23):9570-80
references.pmid: 21118966
references.citation: Mol Cell Biol. 1997 Feb;17(2):799-808
references.pmid: 9001234
references.citation: Lab Invest. 2011 Jan;91(1):124-37
references.pmid: 20661229
references.citation: Head Neck. 2011 Jun;33(6):786-91
references.pmid: 21560177
references.citation: Cancer Res. 2010 Feb 15;70(4):1635-44
references.pmid: 20145132
references.citation: Cancer Res. 2008 Dec 15;68(24):10307-14
references.pmid: 19074899
references.citation: J Clin Invest. 1997 Sep 1;100(5):1282-93
references.pmid: 9276747
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Cancer Cell. 2010 Jan 19;17(1):77-88
references.pmid: 20129249
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11737-42
references.pmid: 11562465
references.citation: Cell. 2009 Jun 12;137(6):1032-46
references.pmid: 19524507
references.citation: Trends Pharmacol Sci. 1992 Apr;13(4):134-6
references.pmid: 1350385
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references.pmid: 16885212
references.citation: Gynecol Oncol. 2001 Sep;82(3):489-97
references.pmid: 11520145
references.citation: J Biol Chem. 2010 Jul 9;285(28):21496-507
references.pmid: 20460378
references.citation: Int J Gynaecol Obstet. 2000 Aug;70(2):209-62
references.pmid: 11041682
references.citation: J Biol Chem. 1994 Apr 1;269(13):9582-9
references.pmid: 8144545
references.citation: Clin Cancer Res. 2011 Jun 15;17(12):4042-51
references.pmid: 21551255