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Insulin Receptor Substrate-1 Deficiency Promotes Apoptosis in the Putative Intestinal Crypt Stem Cell Region, Limits Apc^min/+ Tumors, and Regulates Sox9

Departments of Cell and Molecular Physiology (N.M.R., H.R.W., J.G.S., B.P.S., K.K.M., P.K.L.) and Medicine (S.T.M., G.H.L.), University of North Carolina, Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Nicole M. Ramocki or P. Kay Lund, CB7545, Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545. E-mail: nicole_ramocki{at}med.unc.edu or empk{at}med.unc.edu.

Reduced apoptosis of crypt stem/progenitor cells and elevated insulin and IGFs are linked to colon cancer risk. Insulin receptor substrate-1 (IRS-1) mediates the actions of insulin, IGF-I, and IGF-II, but the role of endogenous IRS-1 in crypt apoptosis and cancer is undefined. Using IRS-1^–/–, IRS-1^+/–, and IRS-1^+/+ mice, we tested the hypothesis that reduced IRS-1 expression increases apoptosis of intestinal crypt cells and protects against Apc^min/+ (Min)/β-catenin-driven intestinal tumors. Expression of Sox9, a transcriptional target of Tcf/β-catenin and putative biomarker of crypt stem cells, was assessed in intestine of different IRS-1 genotypes and cell lines. Irradiation-induced apoptosis was significantly increased in the crypts and crypt stem cell region of IRS-1-deficient mice. Tumor load was significantly reduced by 31.2 ± 14.6% in IRS-1^+/–/Min and by 64.1 ± 7.6% in IRS-1^–/–/Min mice, with more prominent reductions in tumor number than size. Compared with IRS-1^+/+/Min, IRS-1^–/–/Min mice had fewer Sox9-positive cells in intestinal crypts and reduced Sox9 mRNA in intestine. IRS-1 overexpression increased Sox9 expression in an intestinal epithelial cell line. We conclude that even small reductions in endogenous IRS-1 increase apoptosis of crypt stem or progenitor cells, protect against β-catenin-driven intestinal tumors, and reduce Sox9, a Tcf/β-catenin target and putative stem/progenitor cell biomarker.

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