Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9

Abstract

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 Apcmin/+ (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. Copyright © 2008 by The Endocrine Society.