IRS-1 and SOCS2 are key regulators of insulin-like growth factor signaling in intestinal cancer Public Deposited

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  • March 21, 2019
  • Ramocki, Nicole Marie
    • Affiliation: College of Arts and Sciences, School of Medicine, Department of Cell Biology and Physiology
  • The growth hormone/insulin-like growth factor (GH/IGF) axis has been implicated at various stages of tumor progression in colon cancer. Insulin receptor substrate-1 (IRS-1) is a major downstream signaling molecule of insulin, IGF-I, and IGF-II and is constitutively active in various tumor types, including breast. Its role in colon cancer has not been studied in vivo to date. Conversely, Suppressor of Cytokine Signaling-2 (SOCS2) has been shown to limit this pathway and could thereby limit tumorigenesis in intestine. IRS-1 and SOCS2 deficient mice were crossbred with the ApcMin/+ model of intestinal polyposis to test whether IRS-1 or SOCS2 play a role in tumor formation in intestine. SOCS2 deficient mice were crossbred with GH-transgenic mice to test the hypothesis that SOCS2 normally limits GH-mediated trophic and tumorigenic actions. In mice with partial and absolute IRS-1 deficiency, intestinal crypt apoptosis levels were significantly increased, most notably in the putative stem cell region. Partial and absolute IRS-1 deficiency also lead to decreased tumor formation and decreased expression of a putative stem cell marker and [beta]-catenin transcriptional target, Sox9, in intestine of ApcMin/+ mice. Partial SOCS2 deficiency in GH-transgenic mice lead to greater intestinal growth. SOCS2 deficiency lead to greater tumorigenesis in intestine of GH-transgenic and ApcMin/+ mice, but not using the AOM/DSS model of inflammation-associated colon cancer. Overall, these studies suggest that IRS-1 plays a significant role in intestinal tumorigenesis and SOCS2 may serve as a crucial tumor suppressor by limiting the actions of the GH/IGF-I and IRS-1 pathway. Future studies will be aimed at determining if IRS-1, Sox9, and SOCS2 levels in human intestine can serve as useful biomarkers of colon cancer or adenoma risk.
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  • Lund, Pauline Kay
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  • University of North Carolina at Chapel Hill
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