title: A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion.
abstract: BACKGROUND
  The transcription factor nuclear factor-κB (NF-κB) has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3) in controlling metastatic potential of gastric cancer cells.
  
  
  METHODS
  Immunohistochemistry for NF-κB p65 (RelA), phospho-Tyr705-STAT3 (pSTAT3), or matrix metalloproteinase 9 (MMP9) was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively.
  
  
  RESULTS
  NF-κB and STAT3 were constitutively activated and were positively correlated (P=0.038) in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P=0.001 and P=0.022, respectively), decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells.
  
  
  CONCLUSIONS
  NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
authors: Department of Anatomy, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors: Jiyeon
authors: J
authors: Yoon
authors: Sung Jin
authors: SJ
authors: Cho
authors: Young San
authors: YS
authors: Ko
authors: Jinju
authors: J
authors: Park
authors: Dong Hoon
authors: DH
authors: Shin
authors: In Chan
authors: IC
authors: Hwang
authors: Sang Yeun
authors: SY
authors: Han
authors: Seon Young
authors: SY
authors: Nam
authors: Min A
authors: MA
authors: Kim
authors: Mee Soo
authors: MS
authors: Chang
authors: Hye Seung
authors: HS
authors: Lee
authors: Woo Ho
authors: WH
authors: Kim
authors: Byung Lan
authors: BL
authors: Lee
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D066298:In Vitro Techniques; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D014162:Transfection
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020780:Matrix Metalloproteinase 9
references: Genes Nutr. 2012 Apr;7(2):111-25
references: 22274779
references: J Surg Oncol. 2008 Apr 1;97(5):439-44
references: 18163448
references: Oncogene. 1999 Nov 22;18(49):6853-66
references: 10602461
references: Cancer Sci. 2010 Jul;101(7):1653-60
references: 20491781
references: Cancer Cell. 2010 Mar 16;17(3):286-97
references: 20227042
references: J Pathol. 2003 May;200(1):39-46
references: 12692839
references: Trends Genet. 2008 Sep;24(9):448-56
references: 18674843
references: World J Gastroenterol. 2012 Mar 7;18(9):979-85
references: 22408359
references: Cancer Res. 1991 Nov 1;51(21):5800-5
references: 1933850
references: Dig Dis Sci. 2003 Dec;48(12):2290-300
references: 14714615
references: Genes Dev. 2007 Jun 1;21(11):1396-408
references: 17510282
references: J Exp Clin Cancer Res. 2001 Jun;20(2):213-8
references: 11484977
references: Ann N Y Acad Sci. 2009 Aug;1171:59-76
references: 19723038
references: Oncogene. 2012 Jul 19;31(29):3467-81
references: 22105366
references: Cancer Res. 1994 Sep 15;54(18):5005-10
references: 8069868
references: Br J Cancer. 2011 Jul 26;105(3):407-12
references: 21730976
references: J Mol Med (Berl). 2012 Sep;90(9):1037-46
references: 22328012
references: Lancet. 2009 Aug 8;374(9688):477-90
references: 19625077
references: Exp Cell Res. 2011 Jul 15;317(12):1746-62
references: 21570392
references: Cancer Res. 1997 Jul 15;57(14):2856-9
references: 9230189
references: Int J Mol Med. 2011 Jul;28(1):115-9
references: 21455558
references: Oncogene. 1999 Nov 22;18(49):6842-4
references: 10602459
references: Mol Cancer Ther. 2012 Feb;11(2):277-87
references: 22203730
references: Pathology. 2007 Jun;39(3):305-18
references: 17558857
references: Int J Cancer. 2011 Aug 15;129(4):887-95
references: 20957628
references: Gut Microbes. 2010 Mar;1(2):109-113
references: 21326919
references: Cancer Res. 2007 Oct 1;67(19):9577-83
references: 17909069
references: Cancer Res. 2001 Jun 1;61(11):4628-35
references: 11389100
references: Ann Clin Lab Sci. 2008 Summer;38(3):195-209
references: 18715846
references: N Engl J Med. 2011 Mar 17;364(11):985-7
references: 21323535
references: Crit Rev Eukaryot Gene Expr. 2011;21(2):143-53
references: 22077153
references: World J Gastroenterol. 2008 Aug 14;14(30):4739-44
references: 18720533
references: Cancer Sci. 2008 Jun;99(6):1117-24
references: 18384434
references: Mol Cancer. 2010 Apr 30;9:97
references: 20433747
references: Cancer Sci. 2011 Jan;102(1):104-10
references: 20946117
references: Histopathology. 2009 Mar;54(4):442-51
references: 19309396
references: J Clin Invest. 2011 May;121(5):1753-67
references: 21490402
references: Int J Cancer. 2011 Oct 1;129(7):1586-98
references: 21128246
references: Oncogene. 2011 Jun 16;30(24):2778-88
references: 21278793
references: Cancer Sci. 2003 Dec;94(12):1066-73
references: 14662022
references: Int J Oncol. 2005 Dec;27(6):1677-83
references: 16273224
references: Int J Biol Sci. 2011 Apr 27;7(5):536-50
references: 21552420
references: Cancer Cell. 2009 Apr 7;15(4):283-93
references: 19345327
references: PLoS One. 2012;7(7):e41312
references: 22844455
references: Int J Colorectal Dis. 2012 Apr;27(4):447-52
references: 22102084
references: Clin Exp Metastasis. 2012 Mar;29(3):263-72
references: 22252121
references: Nat Immunol. 2004 Nov;5(11):1166-74
references: 15489856
references: Mol Cells. 2001 Apr 30;11(2):192-7
references: 11355700
references: Cancer. 2001 Sep 15;92(6):1427-34
references: 11745219