Sun Jane, Wang Dingyan, Jin Tianru
Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada; Division of Cell and Molecular Biology, University Health Network, Canada.
Biochim Biophys Acta. 2010 Mar;1800(3):344-51. doi: 10.1016/j.bbagen.2009.12.007. Epub 2010 Jan 6.
Epidemiological and experimental evidence that support the correlation between Type 2 diabetes mellitus (T2D) and increased risks of colorectal cancer formation have led us to hypothesize the existence of molecular crosstalk between insulin and canonical Wnt signaling pathways. Insulin was shown to stimulate Wnt target gene expression, utilizing the effector of the Wnt signaling pathway. Whether insulin affects expression of components of Wnt pathway has not been extensively examined.
cDNA microarray was utilized to assess the effect of insulin on gene expression profile in the rat intestinal non-cancer IEC-6 cell line, followed by real-time RT-PCR, Western blotting and reporter gene analyses in intestinal cancer and non-cancer cells.
Insulin was shown to alter the expression of a dozen of Wnt pathway related genes including TCF-4 (=TCF7L2) and frizzled- (Fzd-4). The stimulatory effect of insulin on TCF-4 expression was then confirmed by real-time RT-PCR, Western blotting and luciferase reporter analyses, while the activation on Fzd-4 was confirmed by real-time PCR.
Our observations suggest that insulin may crosstalk with the Wnt signaling pathway in a multi-level fashion, involving insulin regulation of the expression of Wnt target genes, a Wnt receptor, as well as mediators of the Wnt signaling pathway.
支持2型糖尿病（T2D）与结直肠癌发生风险增加之间存在关联的流行病学和实验证据，促使我们推测胰岛素与经典Wnt信号通路之间存在分子串扰。研究表明，胰岛素可利用Wnt信号通路的效应器来刺激Wnt靶基因表达。胰岛素是否影响Wnt通路组分的表达尚未得到广泛研究。
利用cDNA微阵列评估胰岛素对大鼠肠道非癌IEC-6细胞系基因表达谱的影响，随后在肠道癌细胞和非癌细胞中进行实时RT-PCR、蛋白质印迹和报告基因分析。
研究表明，胰岛素可改变包括TCF-4（=TCF7L2）和卷曲蛋白-4（Fzd-4）在内的十几种Wnt通路相关基因的表达。随后通过实时RT-PCR、蛋白质印迹和荧光素酶报告分析证实了胰岛素对TCF-4表达的刺激作用，而通过实时PCR证实了其对Fzd-4的激活作用。
我们的观察结果表明，胰岛素可能以多水平方式与Wnt信号通路发生串扰，涉及胰岛素对Wnt靶基因、Wnt受体以及Wnt信号通路介质表达的调节。
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