Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation
Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation
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DOI：
10.1242/jcs.132985
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发表时间：
2013-12-15
影响因子：
4
通讯作者：
Lund, P. Kay
中科院分区：
文献类型：
--
作者：
Andres, Sarah F.;Simmons, James G.;Lund, P. Kay
尽管有证据表明胰岛素对肠上皮生理和病理生理有影响，但胰岛素受体(IR)及其异构体在肠上皮中的表达模式、作用和调节尚不清楚。IR-A被认为介导了胰岛素或胰岛素生长因子(IGF)对胎儿或癌细胞的增殖作用。IR-B被认为是胰岛素在特定组织中的代谢受体。这项研究使用了一种新型的Sox9-EGFP报告小鼠，它可以分离肠上皮干细胞(IESCs)、祖细胞、肠内分泌细胞和分化的谱系，APC(Min/+)小鼠的癌前病变模型和正常的人类肠道和结直肠癌(CRC)细胞系。我们验证了IR-A或IR-B在干细胞和肿瘤细胞与分化的肠上皮细胞(IECS)中存在差异表达的假设，以及IR-B影响细胞增殖的假设。我们的发现提供了证据，在高增殖的IESCs和前体细胞中，IR-B的表达显著低于有丝分裂后、分化后的IECs，以及在亚融合和未分化的Caco-2细胞中的表达。IR-B在APC(Min/+)肿瘤和高致瘤性CRC细胞中也减少。IR-B的这些差异伴随着编码肌红蛋白样蛋白2(MBNL2)的mRNAs水平的变化，MBNL2是IR选择性剪接的一种已知调节因子。在次融合和未分化的Caco-2细胞中强制表达IR-B减少了增殖并增加了分化的生物标志物。我们的发现表明，胰岛素对肠上皮不同细胞类型的影响可能取决于IR-B：IR-A的相对表达水平，并为IR-B限制结直肠癌细胞增殖的作用提供了新的证据。
Despite evidence for the impact of insulin on intestinal epithelial physiology and pathophysiology, the expression patterns, roles, and regulation of insulin receptor (IR) and IR isoforms in the intestinal epithelium are not well characterized. IR-A is thought to mediate the proliferative effects of insulin or insulin growth factors (IGFs) in fetal or cancer cells. IR-B is considered to be the metabolic receptor for insulin in specialized tissues. This study used a novel Sox9-EGFP reporter mouse that permits isolation of intestinal epithelial stem cells (IESCs), progenitors, enteroendocrine cells and differentiated lineages, the Apc(Min/+) mouse model of precancerous adenoma and normal human intestinal and colorectal cancer (CRC) cell lines. We tested the hypothesis that there is differential expression of IR-A or IR-B in stem and tumor cells versus differentiated intestinal epithelial cells (IECs) and that IR-B impacts cell proliferation. Our findings provide evidence that IR-B expression is significantly lower in highly proliferative IESCs and progenitor cells versus post-mitotic, differentiated IECs and in subconfluent and undifferentiated versus differentiated Caco-2 cells. IR-B is also reduced in Apc(Min/+) tumors and highly tumorigenic CRC cells. These differences in IR-B were accompanied by altered levels of mRNAs encoding muscleblind-like 2 (MBNL2), a known regulator of IR alternative splicing. Forced IR-B expression in subconfluent and undifferentiated Caco-2 cells reduced proliferation and increased biomarkers of differentiation. Our findings indicate that the impact of insulin on different cell types in the intestinal epithelium might differ depending on relative IR-B: IR-A expression levels and provide new evidence for the roles of IR-B to limit proliferation of CRC cells.