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Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

Oncogene volume 26, pages 4833–4841 (2007)Cite this article

Abstract

Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppressor of cytokine signaling-3 (SOCS3) is such a factor. Mice with Vilin-promoter/Cre-recombinase (VC)-mediated IEC-specific SOCS3 gene disruption (VC/HO), WT/HO littermates with floxed but intact SOCS3 genes and VC/WT mice were studied. Colon was examined after acute dextran sodium sulfate (DSS)-induced mucosal injury or after azoxymethane (AOM) and chronic DSS. Signaling pathways were examined in colon, cultured IEC or colon cancer cell lines. VC/HO mice showed no basal phenotype. After acute DSS, VC/HO exhibited enhanced crypt proliferation and crypt hyperplasia and reduced transforming growth factor (TGF) β expression in colon. Inflammation and mucosal damage were similar across genotypes. Following AOM/DSS, VC/HO mice had increased size, number and load of colonic tumors and increased STAT3 and nuclear factor-kappa B (NF-κB) activation in colon. In vitro, SOCS3 overexpression reduced proliferation, IL-6-mediated STAT3 activation and tumor necrosis factor (TNF) α-mediated NF-κB activation. We conclude that cytokine induction of SOCS3 normally provides an intrinsic mechanism to limit injury-induced crypt hyperproliferation and inflammation-associated colon cancer by regulating both STAT3 and NF-κB pathways.

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References

  • Alonzi T, Newton IP, Bryce PJ, Di Carlo E, Lattanzio G, Tripodi M et al. (2004). Induced somatic inactivation of STAT3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine 26: 45–56.

    Article  CAS  PubMed  Google Scholar 

  • Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A et al. (2004). TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21: 491–501.

    Article  CAS  PubMed  Google Scholar 

  • Campbell JS, Prichard L, Schaper F, Schmitz J, Stephenson-Famy A, Rosenfeld ME et al. (2001). Expression of suppressors of cytokine signaling during liver regeneration. J Clin Invest 107: 1285–1292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C et al. (2006). Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 103: 8137–8142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung YC, Chang YF . (2003). Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 83: 222–226.

    Article  PubMed  Google Scholar 

  • Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG et al. (2003). SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4: 540–545.

    Article  CAS  PubMed  Google Scholar 

  • Greenhalgh CJ, Miller ME, Hilton DJ, Lund PK . (2002). Suppressors of cytokine signaling: relevance to gastrointestinal function and disease. Gastroenterology 123: 2064–2081.

    Article  CAS  PubMed  Google Scholar 

  • Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K et al. (2006). IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203: 1391–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He B, You L, Uematsu K, Zang K, Xu Z, Lee AY et al. (2003). SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100: 14133–14138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F . (2003). Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374: 1–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itzkowitz S . (2003). Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice. J Clin Gastroenterol 36: 70–74.

    Article  Google Scholar 

  • Judd LM, Alderman BM, Howlett M, Shulkes A, Dow C, Moverley J et al. (2004). Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology 126: 196–207.

    Article  CAS  PubMed  Google Scholar 

  • Judd LM, Bredin K, Kalantzis A, Jenkins BJ, Ernst M, Giraud AS . (2006). STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis. Gastroenterology 131: 1073–1085.

    Article  CAS  PubMed  Google Scholar 

  • Kimura A, Naka T, Nagata S, Kawase I, Kishimoto T . (2004). SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak activation. Int Immunol 16: 991–999.

    Article  CAS  PubMed  Google Scholar 

  • Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, de Oca J et al. (2003). Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res 63: 3560–3566.

    CAS  PubMed  Google Scholar 

  • Miller ME, Goebel HN, Williams KL, Keku TO, Pucilowska JB, Sartor RB et al. (2000). Suppressor of cytokine signalling-3 (SOCS-3) mRNA is preferentially induced during experimental enterocolitis, ulcerative colitis and Crohn's disease. Regulatory Peptides 94: 67–68.

    Article  Google Scholar 

  • Miller ME, Michaylira CZ, Simmons JG, Ney DM, Dahly EM, Heath JK et al. (2004). Suppressor of cytokine signaling-2: a growth hormone-inducible inhibitor of intestinal epithelial cell proliferation. Gastroenterology 127: 570–581.

    Article  CAS  PubMed  Google Scholar 

  • Miscia S, Marchisio M, Grilli A, Di VV, Centurione L, Sabatino G et al. (2002). Tumor necrosis factor alpha (TNF-alpha) activates Jak1/Stat3-Stat5B signaling through TNFR-1 in human B cells. Cell Growth Differ 13: 13–18.

    CAS  PubMed  Google Scholar 

  • Mizoguchi E, Xavier RJ, Reinecker HC, Uchino H, Bhan AK, Podolsky DK et al. (2003). Colonic epithelial functional phenotype varies with type and phase of experimental colitis. Gastroenterology 125: 148–161.

    Article  CAS  PubMed  Google Scholar 

  • Munkholm P . (2003). Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 18(Suppl 2): 1–5.

    Article  PubMed  Google Scholar 

  • Nakamura Y, Chang CC, Mori T, Sato K, Ohtsuki K, Upham BL et al. (2004). Augmentation of differentiation and gap junction function by kaempferol in partially-differentiated colon cancer cells. Carcinogenesis 26: 665–671.

    Article  PubMed  Google Scholar 

  • Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T et al. (2005). Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24: 6406–6417.

    Article  CAS  PubMed  Google Scholar 

  • Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H et al. (2006a). Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene 25: 2520–2530.

    Article  CAS  PubMed  Google Scholar 

  • Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y et al. (2006b). Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131: 179–193.

    Article  CAS  PubMed  Google Scholar 

  • Oshimo Y, Kuraoka K, Nakayama H, Kitadai Y, Yoshida K, Chayama K et al. (2004). Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Int J Cancer 112: 1003–1009.

    Article  CAS  PubMed  Google Scholar 

  • Rivat C, Wever OD, Bruyneel E, Mareel M, Gespach C, Attoub S . (2004). Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell-cell adhesion complexes. Oncogene 23: 3317–3327.

    Article  CAS  PubMed  Google Scholar 

  • Schneider MR, Hoeflich A, Fischer JR, Wolf E, Sordat B, Lahm H . (2000). Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells. Cancer Lett 151: 31–38.

    Article  CAS  PubMed  Google Scholar 

  • Sutherland KD, Lindeman GJ, Choong DY, Wittlin S, Brentzell L, Phillips W et al. (2004). Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene 23: 7726–7733.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T et al. (2001). CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 193: 471–481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ et al. (2002). Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8: 1089–1097.

    Article  CAS  PubMed  Google Scholar 

  • Ulshen MH, Dowling RH, Fuller CR, Zimmermann EM, Lund PK . (1993). Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone. Gastroenterology 104: 973–980.

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Walia B, Evans J, Gewirtz AT, Merlin D, Sitaraman SV . (2003). IL-6 induces NF-kappa B activation in the intestinal epithelia. J Immunol 171: 3194–3201.

    Article  CAS  PubMed  Google Scholar 

  • Weber A, Hengge UR, Bardenheuer W, Tischoff I, Sommerer F, Markwarth A et al. (2005). SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene 24: 6699–6708.

    Article  CAS  PubMed  Google Scholar 

  • Williams KL, Fuller CR, Dieleman LA, DaCosta CM, Haldeman KM, Sartor RB et al. (2001). Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology 120: 925–937.

    Article  CAS  PubMed  Google Scholar 

  • Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D et al. (2003). IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4: 551–556.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Kirk McNaughton for assistance with histology and immunohistochemistry, Dr Daniel Meechan for help with real-time PCR, Victoria Newton for assistance with BrdU cell counting and Eileen Hoyt for guidance with EMSA assays. This work was supported by a senior research award and post-doctoral fellowship from the Crohns' and Colitis foundation of America. Gene therapy and imaging core facilities of the Center for Gastrointestinal Biology and Disease (#P30 DK34987) assisted this work. We thank Dr Richard Furlanetto and Dr Robert Coffrey for provision of plasmids and cells.

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  1. Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC, USA

    R J Rigby, J G Simmons & P K Lund

  2. Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

    C J Greenhalgh

  3. Division of Autoimmunity and Transplantation, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

    W S Alexander

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  1. R J Rigby
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Correspondence to R J Rigby.

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Rigby, R., Simmons, J., Greenhalgh, C. et al. Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 26, 4833–4841 (2007). https://doi.org/10.1038/sj.onc.1210286

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