Inflammatory bowel diseases (IBD) involve chronic destruction of the intestinal epithelium, and compensatory crypt regeneration and hyperplasia. During IBD, mitogenic and anti-apoptotic effects of cytokines and growth factors help to maintain or restore functional epithelial mass. These same mechanisms, if excessive or prolonged, may promote dysplasia and neoplasia. This proposal will test a central hypothesis that silencing of SOCS3 in intestinal epithelial cells (IEC) promotes inflammation- associated dysplasia and tumorigenesis by limiting the activation of multiple pro-tumorigenic pathways. Preliminary data support a working model that IEC-SOCS3 silencing promotes tumorigenesis by limiting excessive or aberrant activation of STATs, NFkB and TNF receptor 2 (TNFR2).
Aim 1 will define the cellular and molecular mechanisms and gene targets associated with enhanced AOM/DSS-induced tumorigenesis in mice with IEC-SOCS3 deletion. Mice with IEC-specific SOCS3 disruption show increased tumor number and size after AOM/DSS. Biochemical, molecular and gene microarray studies will test if loss of SOCS3 enhances activation of STAT and NFkB and their downstream genetic targets, including TNFR2, or novel oncogenic mediators.
Aim 2 will define the direct effects of SOCS3 on pro-tumorigenic signaling or transcriptional pathways in IEC or colon cancer cells, and their relevance to tumor cell growth or survival. Non- transformed IEC-6 cells and colon cancer cell lines expressing different levels of endogenous or transgene derived SOCS3, or mutant SOCS3 isoforms, will be used to define mechanisms of action of SOCS3. Constitutive activation or expression of STAT, NFkB or TNFR2, or specific inhibitors of these mediators, will be tested for their ability to reverse the phenotypic or transcriptional effects of SOCS3 over-expression or silencing.
Aim #3 will confirm that IEC-SOCS3 deletion promotes dysplasia and tumorigenesis in the IL- 10 null model of IBD and define mechanisms. Mice with combined IEC-specific SOCS3 disruption and IL-10 gene deletion will be used to confirm preliminary data that loss of IEC-SOCS3 promotes spontaneous small bowel tumors and inflammation-associated colon tumors. Biochemical and molecular analyses will test whether similar or distinct signaling pathways and gene targets are affected by SOCS3 in the IL-10 null versus AOM/DSS model Follow up studies will use information from aims 1-3 to design experiments using pharmacological or genetic manipulation of STAT, NF:B or TNFR2 in AOM/DSS or IL-10 null models and define the functional in vivo role of these mediators in transcriptional or tumor-promoting effects of IEC-SOCS3 deletion.
Patients with the inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease have increased colon cancer risk, and chronic inflammation is increasingly linked to cancer. This project tests whether a naturally occurring body protein, suppressor of cytokine signaling 3 (SOCS3), normally reduces or prevents development of colon tumors during intestinal inflammation, and if SOCS3 limits the actions of several molecules known to cause colon cancer. The results will guide and promote use of SOCS3 as a biomarker for cancer risk and assist the development of SOCS3-based therapies as new approaches to prevent colon cancer in IBD.
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|Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong et al. (2016) The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell Rep 14:2562-75|
|Ding, Shengli; Blue, Randal E; Morgan, Douglas R et al. (2014) Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models. Inflamm Bowel Dis 20:363-77|
|Hamilton, Kathryn E; Tétreault, Marie-Pier; Lund, P Kay (2013) Opportunities and challenges for women PhD investigators in gastrointestinal research. Gastroenterology 145:266-71|
|Van Landeghem, Laurianne; Santoro, M Agostina; Krebs, Adrienne E et al. (2012) Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am J Physiol Gastrointest Liver Physiol 302:G1111-32|
|Ding, Shengli; Eric Blue, Randall; Chen, Yijing et al. (2012) Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probes. Mol Imaging 11:507-15|
|Ding, Shengli; Walton, Kristen L W; Blue, Randall Eric et al. (2012) Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen ?1(I)-promoter-GFP reporter mice. PLoS One 7:e42568|
|Bortvedt, Sarah F; Lund, P Kay (2012) Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors. Curr Opin Gastroenterol 28:89-98|
|Ding, Shengli; Lund, Pauline K (2011) Role of intestinal inflammation as an early event in obesity and insulin resistance. Curr Opin Clin Nutr Metab Care 14:328-33|
|Azcárate-Peril, M Andrea; Sikes, Michael; Bruno-Bárcena, José M (2011) The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol 301:G401-24|
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