STAT1 and STAT3 Transcription Factors in Inflammation-associated Colon Cancer

  • Paulina Rampetsreiter
  • Robert EferlEmail author


Inflammation is a strong promoter of colorectal cancer formation. Colorectal tumor cells establish heterotypic interactions with inflammatory cells in the stroma that are important for tumor angiogenesis and invasiveness. Recent studies in genetically modified mice have identified transcription factors and signaling networks that are implicated in these heterotypic tumor-stroma interactions and modulate preconditions of tumor formation such as chronic inflammation. Here, tumor-promoting and tumor-adverse effects of cytokine-activated transcription factors STAT1 and STAT3 in inflammatory cells and colorectal cancer cells are discussed.


Adenomatous Polyposis Coli Inflammatory Bowel Disease Patient Colon Cancer Cell Line Intestinal Tumor Intestinal Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by the Austrian Science Fund FWF grant SFB F28 (RE), GENAU “Austromouse” (RE) and Doktoratskolleg plus IAI (Inflammation and Immunity; RE).


  1. Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O’Shea JJ, Frucht DM (2003) Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol 23:147–161PubMedCrossRefGoogle Scholar
  2. Alonzi T, Newton IP, Bryce PJ, Di Carlo E, Lattanzio G, Tripodi M, Musiani P, Poli V (2004) Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine 26:45–56PubMedCrossRefGoogle Scholar
  3. Amos-Landgraf JM, Kwong LN, Kendziorski CM, Reichelderfer M, Torrealba J, Weichert J, Haag JD, Chen KS, Waller JL, Gould MN et al (2007) A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA 104:4036–4041PubMedCrossRefGoogle Scholar
  4. Bandyopadhyay SK, de la Motte CA, Kessler SP, Hascall VC, Hill DR, Strong SA (2008) Hyaluronan-mediated leukocyte adhesion and dextran sulfate sodium-induced colitis are attenuated in the absence of signal transducer and activator of transcription 1. Am J Pathol 173:1361–1368PubMedCrossRefGoogle Scholar
  5. Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S et al (2004) TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21:491–501PubMedCrossRefGoogle Scholar
  6. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102PubMedCrossRefGoogle Scholar
  7. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303PubMedCrossRefGoogle Scholar
  8. Cheon H, Yang J, Stark GR (2011) The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins. J Interferon Cytokine Res 31:33–40PubMedCrossRefGoogle Scholar
  9. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073–1081PubMedCrossRefGoogle Scholar
  10. Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K et al (2005) Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 7:545–555PubMedCrossRefGoogle Scholar
  11. de Lau W, Barker N, Clevers H (2007) WNT signaling in the normal intestine and colorectal cancer. Front Biosci 12:471–491PubMedCrossRefGoogle Scholar
  12. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science (New York) 324:1713–1716CrossRefGoogle Scholar
  13. Gregersen LH, Jacobsen AB, Frankel LB, Wen J, Krogh A, Lund AH (2010) MicroRNA-145 targets YES and STAT1 in colon cancer cells. PLoS One 5:e8836PubMedCrossRefGoogle Scholar
  14. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedCrossRefGoogle Scholar
  15. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113PubMedCrossRefGoogle Scholar
  16. Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H et al (2006) IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203:1391–1397PubMedCrossRefGoogle Scholar
  17. Horino J, Fujimoto M, Terabe F, Serada S, Takahashi T, Soma Y, Tanaka K, Chinen T, Yoshimura A, Nomura S et al (2008) Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunol 20:753–762PubMedCrossRefGoogle Scholar
  18. Huang S (2007) Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res 13:1362–1366PubMedCrossRefGoogle Scholar
  19. Kaler P, Augenlicht L, Klampfer L (2009) Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene 28:3892–3902PubMedCrossRefGoogle Scholar
  20. Kawada M, Seno H, Uenoyama Y, Sawabu T, Kanda N, Fukui H, Shimahara Y, Chiba T (2006) Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-catenin in colorectal cancer. Cancer Res 66:2913–2917PubMedCrossRefGoogle Scholar
  21. Klampfer L (2008) The role of signal transducers and activators of transcription in colon cancer. Front Biosci 13:2888–2899PubMedCrossRefGoogle Scholar
  22. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science (New York) 275:1784–1787CrossRefGoogle Scholar
  23. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG et al (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321PubMedCrossRefGoogle Scholar
  24. Kovacic B, Stoiber D, Moriggl R, Weisz E, Ott RG, Kreibich R, Levy DE, Beug H, Freissmuth M, Sexl V (2006) STAT1 acts as a tumor promoter for leukemia development. Cancer Cell 10:77–87PubMedCrossRefGoogle Scholar
  25. Liddle FJ, Frank DA (2008) STAT1 expression is not required for polyp formation in Min mice. Mol Carcinog 47:75–79PubMedCrossRefGoogle Scholar
  26. Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460PubMedCrossRefGoogle Scholar
  27. McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Rocken C, Tanzer M, Ebert MP, Liu K (2008) DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells. Mol Cancer Res 6:1841–1851PubMedGoogle Scholar
  28. Monnien F, Zaki H, Borg C, Mougin C, Bosset JF, Mercier M, Arbez-Gindre F, Kantelip B (2010) Prognostic value of phosphorylated STAT3 in advanced rectal cancer: a study from 104 French patients included in the EORTC 22921 trial. J Clin Pathol 63:873–878PubMedCrossRefGoogle Scholar
  29. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science (New York) 275:1787–1790CrossRefGoogle Scholar
  30. Murray PJ (2007) The JAK-STAT signaling pathway: input and output integration. J Immunol 178:2623–2629PubMedGoogle Scholar
  31. Musteanu M, Blaas L, Mair M, Schlederer M, Bilban M, Tauber S, Esterbauer H, Mueller M, Casanova E, Kenner L et al (2010) Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology 138:1003–1011, e1001–1005PubMedCrossRefGoogle Scholar
  32. O’Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC (2007) Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 44:2497–2506PubMedCrossRefGoogle Scholar
  33. Poole AJ, Heap D, Carroll RE, Tyner AL (2004) Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 23:8128–8134PubMedCrossRefGoogle Scholar
  34. Regis G, Pensa S, Boselli D, Novelli F, Poli V (2008) Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol 19:351–359PubMedCrossRefGoogle Scholar
  35. Rigby RJ, Simmons JG, Greenhalgh CJ, Alexander WS, Lund PK (2007) Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 26:4833–4841PubMedCrossRefGoogle Scholar
  36. Rivat C, Rodrigues S, Bruyneel E, Pietu G, Robert A, Redeuilh G, Bracke M, Gespach C, Attoub S (2005) Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) – and vascular endothelial growth factor-mediated cellular invasion and tumor growth. Cancer Res 65:195–202PubMedGoogle Scholar
  37. Rosenberg DW, Giardina C, Tanaka T (2009) Mouse models for the study of colon carcinogenesis. Carcinogenesis 30:183–196PubMedCrossRefGoogle Scholar
  38. Rustgi AK (2007) The genetics of hereditary colon cancer. Genes Dev 21:2525–2538PubMedCrossRefGoogle Scholar
  39. Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP, Batlle E, Simon-Assmann P, Clevers H, Nathke IS et al (2004) Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18:1385–1390PubMedCrossRefGoogle Scholar
  40. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–418PubMedCrossRefGoogle Scholar
  41. Schreiber S, Rosenstiel P, Hampe J, Nikolaus S, Groessner B, Schottelius A, Kuhbacher T, Hamling J, Folsch UR, Seegert D (2002) Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut 51:379–385PubMedCrossRefGoogle Scholar
  42. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111PubMedCrossRefGoogle Scholar
  43. Simpson JA, Al-Attar A, Watson NF, Scholefield JH, Ilyas M, Durrant LG (2010) Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer. Gut 59:926–933PubMedCrossRefGoogle Scholar
  44. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–49PubMedCrossRefGoogle Scholar
  45. Terzic J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138:2101–2114, e2105PubMedCrossRefGoogle Scholar
  46. Tsareva SA, Moriggl R, Corvinus FM, Wiederanders B, Schutz A, Kovacic B, Friedrich K (2007) Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia 9:279–291PubMedCrossRefGoogle Scholar
  47. Uronis JM, Threadgill DW (2009) Murine models of colorectal cancer. Mamm Genome 20:261–268PubMedCrossRefGoogle Scholar
  48. Yang W, Velcich A, Mariadason J, Nicholas C, Corner G, Houston M, Edelmann W, Kucherlapati R, Holt PR, Augenlicht LH (2001) p21(WAF1/cip1) is an important determinant of intestinal cell response to sulindac in vitro and in vivo. Cancer Res 61:6297–6302PubMedGoogle Scholar
  49. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 21:1396–1408PubMedCrossRefGoogle Scholar
  50. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev 7:41–51CrossRefGoogle Scholar
  51. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  1. 1.Ludwig Boltzmann Institute for Cancer Research (LBICR)ViennaAustria
  2. 2.Institute for Cancer Research, Medical University of Vienna (MUV)ViennaAustria

Personalised recommendations