title: Fibroblast growth factor 2 induces E-cadherin down-regulation via PI3K/Akt/mTOR and MAPK/ERK signaling in ovarian cancer cells.
abstract: Fibroblast growth factor 2 (FGF2) is produced by ovarian cancer cells and it has been suggested to play an important role in tumor progression. In this study, we report that FGF2 treatment down-regulated E-cadherin by up-regulating its transcriptional repressors, Slug and ZEB1, in human ovarian cancer cells. The pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), and MEK suggests that both PI3K/Akt/mTOR and MAPK/ERK signaling are required for FGF2-induced E-cadherin down-regulation. Moreover, FGF2 up-regulated Slug and ZEB1 expression via the PI3K/Akt/mTOR and MAPK/ERK signaling pathways, respectively. Finally, FGF2-induced cell invasion was abolished by the inhibition of the PI3K/Akt/mTOR and MAPK/ERK pathways, and the forced expression of E-cadherin diminished the intrinsic invasiveness of ovarian cancer cells as well as the FGF2-induced cell invasion. This study demonstrates a novel mechanism in which FGF2 down-regulates E-cadherin expression through the activation of PI3K/Akt/mTOR and MAPK/ERK signaling, and the up-regulation of Slug and ZEB1 in human ovarian cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Man-Tat
authors.initials: MT
authors.lastname: Lau
authors.forename: Wai-Kin
authors.initials: WK
authors.lastname: So
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D016222:Fibroblast Growth Factor 2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
references.citation: J Cell Biol. 2001 May 28;153(5):1049-60
references.pmid: 11381089
references.citation: Cancer Lett. 1998 Aug 14;130(1-2):69-76
references.pmid: 9751258
references.citation: Br J Cancer. 2010 Jul 27;103(3):370-81
references.pmid: 20606682
references.citation: Diabetes. 2009 Mar;58(3):663-72
references.pmid: 19073772
references.citation: J Cell Biol. 2006 Sep 25;174(7):1087-96
references.pmid: 16982802
references.citation: Clin Exp Metastasis. 2008;25(6):643-55
references.pmid: 18398687
references.citation: J Cell Sci. 2003 Feb 1;116(Pt 3):499-511
references.pmid: 12508111
references.citation: Br J Cancer. 2001 Jun 15;84(12):1656-63
references.pmid: 11401320
references.citation: Cancer Res. 2008 Apr 1;68(7):2479-88
references.pmid: 18381457
references.citation: Clin Exp Metastasis. 2010 Mar;27(3):161-72
references.pmid: 20213325
references.citation: Cancer Invest. 1998;16(4):252-61
references.pmid: 9589034
references.citation: Clin Cancer Res. 1997 Sep;3(9):1579-86
references.pmid: 9815846
references.citation: Nat Cell Biol. 2000 Feb;2(2):84-9
references.pmid: 10655587
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15406-11
references.pmid: 9860981
references.citation: Nat Rev Cancer. 2007 Jun;7(6):415-28
references.pmid: 17508028
references.citation: Differentiation. 2008 Feb;76(2):193-205
references.pmid: 17608733
references.citation: Br J Cancer. 1997;76(2):238-43
references.pmid: 9231925
references.citation: J Cell Biochem. 2005 Oct 1;96(2):221-34
references.pmid: 16088943
references.citation: Virchows Arch. 2006 Nov;449(5):520-8
references.pmid: 17024425
references.citation: Mol Cell. 2001 Jun;7(6):1267-78
references.pmid: 11430829
references.citation: Mol Cell. 2010 Apr 9;38(1):114-27
references.pmid: 20385094
references.citation: Am J Pathol. 2009 Jun;174(6):2107-15
references.pmid: 19389926
references.citation: Oncogene. 2004 Oct 21;23(49):8171-83
references.pmid: 15377994
references.citation: Hematol Oncol Clin North Am. 2003 Aug;17(4):927-43
references.pmid: 12959183
references.citation: Int J Biochem Cell Biol. 2009 Jun;41(6):1323-31
references.pmid: 19110070
references.citation: Oncogene. 2011 Oct 27;30(43):4410-27
references.pmid: 21532623
references.citation: Am J Pathol. 2003 Jun;162(6):1913-26
references.pmid: 12759248
references.citation: Int J Cancer. 1994 Aug 1;58(3):393-9
references.pmid: 7519585
references.citation: Mol Biol Cell. 2004 Oct;15(10):4725-34
references.pmid: 15282342
references.citation: Oncogene. 2000 Aug 3;19(33):3823-8
references.pmid: 10949939
references.citation: Gynecol Oncol. 2007 Jul;106(1):221-32
references.pmid: 17481705
references.citation: J Cell Biol. 1998 Jul 27;142(2):557-71
references.pmid: 9679152
references.citation: Cancer Res. 2008 Apr 1;68(7):2329-39
references.pmid: 18381440
references.citation: Cancer Lett. 2012 Dec 30;326(2):191-8
references.pmid: 22922215
references.citation: Am J Obstet Gynecol. 1993 Dec;169(6):1517-23
references.pmid: 8267056
references.citation: Cancer Res. 1999 Aug 1;59(15):3552-6
references.pmid: 10446959
references.citation: Eur J Gynaecol Oncol. 1997;18(5):349-52
references.pmid: 9378151
references.citation: Cancer Res. 1995 Nov 15;55(22):5195-9
references.pmid: 7585573
references.citation: J Biol Chem. 2006 Oct 27;281(43):32217-26
references.pmid: 16940294
references.citation: J Biol Chem. 2001 Jun 22;276(25):22565-72
references.pmid: 11312273
references.citation: Oncogene. 2011 Jun 16;30(24):2753-66
references.pmid: 21297666
references.citation: Gynecol Oncol. 1994 Nov;55(2):277-84
references.pmid: 7959296
references.citation: Nat Cell Biol. 2000 Feb;2(2):76-83
references.pmid: 10655586
references.citation: Pharm Biol. 2010 Feb;48(2):161-5
references.pmid: 20645833
references.citation: CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30
references.pmid: 15661684
references.citation: Genes Chromosomes Cancer. 2002 Jul;34(3):255-68
references.pmid: 12007186
references.citation: J Urol. 2004 Oct;172(4 Pt 1):1333-7
references.pmid: 15371835
references.citation: Mol Cell Endocrinol. 2002 Feb 22;187(1-2):39-45
references.pmid: 11988310
references.citation: Angiogenesis. 2004;7(1):29-32
references.pmid: 15302993
references.citation: Cancer Res. 2005 Feb 15;65(4):1325-34
references.pmid: 15735018
references.citation: Clin Exp Metastasis. 2006;23(1):65-74
references.pmid: 16826427
references.citation: Exp Cell Res. 2008 Feb 1;314(3):421-9
references.pmid: 18164704
references.citation: J Surg Res. 2003 Nov;115(1):113-20
references.pmid: 14572781
references.citation: Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2358-68
references.pmid: 16723445
references.citation: Science. 2004 Nov 26;306(5701):1506-7
references.pmid: 15567848
references.citation: Otol Neurotol. 2011 Feb;32(2):308-14
references.pmid: 21178801
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49
references.pmid: 15863030
references.citation: Mol Cell Biol Res Commun. 1999 Aug;2(2):77-85
references.pmid: 10542129
references.citation: Endocr Rev. 2005 Feb;26(1):63-77
references.pmid: 15689573
references.citation: Cancer Res. 2002 Mar 15;62(6):1613-8
references.pmid: 11912130
references.citation: Nat Rev Cancer. 2010 Feb;10(2):116-29
references.pmid: 20094046
references.citation: Kidney Int. 2002 May;61(5):1714-28
references.pmid: 11967021
references.citation: Gynecol Oncol. 2005 Apr;97(1):155-65
references.pmid: 15790452
references.citation: Am J Pathol. 2003 Aug;163(2):653-61
references.pmid: 12875984
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: Hum Pathol. 1997 Aug;28(8):922-8
references.pmid: 9269828
references.citation: Oncogene. 1995 Aug 3;11(3):475-84
references.pmid: 7630631
references.citation: Physiol Rev. 2003 Jul;83(3):835-70
references.pmid: 12843410