Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9
Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9
复制标题
DOI：
10.1210/en.2007-0869
复制
发表时间：
2008-01-01
期刊：
影响因子：
4.8
通讯作者：
Lund, P. Kay
中科院分区：
文献类型：
--
作者：
Ramocki, Nicole M.;Wilkins, Heather R.;Lund, P. Kay
隐窝干/祖细胞凋亡减少和胰岛素和IGFs升高与结肠癌风险有关。胰岛素受体底物-1（IRS-1）介导胰岛素、IGF-I和IGF-II的作用，但内源性IRS-1在隐窝凋亡和癌症中的作用尚不明确。使用IRS-1（-/-）、IRS-1（-/-）和IRS-1（-/-）小鼠，我们检验了IRS-1表达减少增加肠隐窝细胞凋亡并保护免受Apc（min/+）（Min）/β-连环蛋白驱动的肠肿瘤的假设。在不同IRS-1基因型和细胞系的肠道中评估了Sox 9的表达，Sox 9是Tcf/β-连环蛋白的转录靶点和隐窝干细胞的假定生物标志物。IRS-1缺陷小鼠的隐窝和隐窝干细胞区域中辐射诱导的细胞凋亡显著增加。IRS-1（+/-）/Min小鼠的肿瘤负荷显著降低了31.2 +/- 14.6%，IRS-1（-/-）/Min小鼠的肿瘤负荷显著降低了64.1 +/- 7.6%，肿瘤数量的减少比肿瘤大小的减少更为显著。与IRS-1（+/+）/Min小鼠相比，IRS-1（-/-）/Min小鼠肠腺Sox 9阳性细胞减少，小肠Sox 9 mRNA表达降低。IRS-1过表达增加肠上皮细胞系中Sox 9的表达。我们的结论是，即使是内源性IRS-1的小幅度减少也会增加隐窝干细胞或祖细胞的凋亡，防止β-连环蛋白驱动的肠道肿瘤，并减少Sox 9，Tcf/β-连环蛋白靶点和推定的干细胞/祖细胞生物标志物。
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)/beta-catenin-driven intestinal tumors. Expression of Sox9, a transcriptional target of Tcf/beta-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 beta-catenindriven intestinal tumors, and reduce Sox9, a Tcf/beta-catenin target and putative stem/progenitor cell biomarker.