Gastroenterology
Volume 138, Issue 3 , Pages 1003-1011.e5 , March 2010

Stat3 Is a Negative Regulator of Intestinal Tumor Progression in ApcMin Mice

  • Monica Musteanu

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  • ,
  • Leander Blaas

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  • ,
  • Markus Mair

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  • ,
  • Michaela Schlederer

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  • ,
  • Martin Bilban

      Affiliations

    • Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
  • ,
  • Stefanie Tauber

      Affiliations

    • Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
  • ,
  • Harald Esterbauer

      Affiliations

    • Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
  • ,
  • Mathias Mueller

      Affiliations

    • Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
  • ,
  • Emilio Casanova

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
  • ,
  • Lukas Kenner

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
    • Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
  • ,
  • Valeria Poli

      Affiliations

    • Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy
  • ,
  • Robert Eferl

      Affiliations

    • Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
    • Corresponding Author InformationReprint requests Address requests for reprints to: Dr Robert Eferl, Ludwig Boltzmann Institute for Cancer Research, Waehringer Strasse 13a, A-1090 Vienna, Austria; fax: +43 1 4277-9641

Received 11 June 2009 ,Accepted 19 November 2009.

References 

  1. Huang CS, O'Brien MJ, Yang S, et al. Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am J Gastroenterol. 2004;99:2242–2255
  2. Clevers H. At the crossroads of inflammation and cancer. Cell. 2004;118:671–674
  3. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–535
  4. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327:293–297
  5. Forrester K, Almoguera C, Han K, et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987;327:298–303
  6. Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006;25:7531–7537
  7. Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–296
  8. Klampfer L. The role of signal transducers and activators of transcription in colon cancer. Front Biosci. 2008;13:2888–2899
  9. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178:2623–2629
  10. Becker C, Fantini MC, Schramm C, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004;21:491–501
  11. Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91–102
  12. Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–113
  13. Rigby RJ, Simmons JG, Greenhalgh CJ, et al. Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene. 2007;26:4833–4841
  14. He B, You L, Uematsu K, et al. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A. 2003;100:14133–14138
  15. Zhang X, Guo A, Yu J, et al. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci U S A. 2007;104:4060–4064
  16. Rebouissou S, Amessou M, Couchy G, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009;457:200–204
  17. Huang S. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res. 2007;13:1362–1366
  18. Horiguchi A, Oya M, Shimada T, et al. Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome. J Urol. 2002;168:762–765
  19. Suiqing C, Min Z, Lirong C. Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma. J Dermatol. 2005;32:354–360
  20. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol. 2005;58:833–838
  21. Fletcher S, Turkson J, Gunning PT. Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. Chem Med Chem. 2008;3:1159–1168
  22. Alonzi T, Maritano D, Gorgoni B, et al. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Mol Cell Biol. 2001;21:1621–1632
  23. el Marjou F, Janssen KP, Chang BH, et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 2004;39:186–193
  24. Su LK, Kinzler KW, Vogelstein B, et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992;256:668–670
  25. Teppner I, Aigner B, Schreiner E, et al. Polymorphic microsatellite markers in the outbred CFW and ICR stocks for the generation of speed congenic mice on C57BL/6 background. Lab Anim. 2004;38:406–412
  26. Boivin GP, Groden J. Mouse models of intestinal cancer. Comp Med. 2004;54:15–18
  27. Irizarry RA, Bolstad BM, Collin F, et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 2003;31:e15
  28. Chiaretti S, Li X, Gentleman R, et al. Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival. Blood. 2004;103:2771–2778
  29. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–5121
  30. Corvinus FM, Orth C, Moriggl R, et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 2005;7:545–555
  31. Abbud RA, Kelleher R, Melmed S. Cell-specific pituitary gene expression profiles after treatment with leukemia inhibitory factor reveal novel modulators for proopiomelanocortin expression. Endocrinology. 2004;145:867–880
  32. Sansom OJ, Reed KR, Hayes AJ, et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 2004;18:1385–1390
  33. Leung N, Turbide C, Balachandra B, et al. Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1-/- mice. Oncogene. 2008;27:4943–4953
  34. Leung N, Turbide C, Olson M, et al. Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis. Oncogene. 2006;25:5527–5536
  35. Nittka S, Gunther J, Ebisch C, et al. The human tumor suppressor CEACAM1 modulates apoptosis and is implicated in early colorectal tumorigenesis. Oncogene. 2004;23:9306–9313
  36. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell. 1999;98:295–303
  37. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 2005;41:2502–2512
  38. Regis G, Pensa S, Boselli D, et al. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol. 2008;19:351–359
  39. Costa-Pereira AP, Tininini S, Strobl B, et al. Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc Natl Acad Sci U S A. 2002;99:8043–8047
  40. Kim HS, Lee MS. STAT1 as a key modulator of cell death. Cell Signal. 2007;19:454–465
  41. Kovacic B, Stoiber D, Moriggl R, et al. STAT1 acts as a tumor promoter for leukemia development. Cancer Cell. 2006;10:77–87
  42. Lin W, Kemper A, McCarthy KD, et al. Interferon-gamma induced medulloblastoma in the developing cerebellum. J Neurosci. 2004;24:10074–10083
  43. Closa D, Motoo Y, Iovanna JL. Pancreatitis-associated protein: from a lectin to an anti-inflammatory cytokine. World J Gastroenterol. 2007;13:170–174
  44. Shively JE. CEACAM1 and hyperplastic polyps: new links in the chain of events leading to colon cancer. Oncogene. 2004;23:9303–9305

 Conflicts of interest The authors disclose no conflicts.

 Funding This work was supported by the Austrian Science Fund FWF grant SFB F28 to R.E. and M. Mueller, the GENAU “Austromouse” Fund to R.E. and E.C., the AIRC (Italian Cancer Research Association) to V.P.

PII: S0016-5085(09)02101-5

doi: 10.1053/j.gastro.2009.11.049

Gastroenterology
Volume 138, Issue 3 , Pages 1003-1011.e5 , March 2010