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Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-β1–Mediated Epithelial-Mesenchymal Transition

¹ Laboratory of Molecular Cell Biology and ² State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

Requests for reprints: Jian-Guo Song, Shanghai Institutes for Biological Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031 China. Phone: 86-21-54921167; Fax: 86-54921167; E-mail: jgsong{at}sibs.ac.cn.

Key Words: EMT • IRS-1 • Snail

We investigated the regulatory effect of insulin receptor substrate-1 (IRS-1) on transforming growth factor-β1 (TGF-β1)–induced epithelial-mesenchymal transition (EMT). TGF-β1–induced EMT and cell migration in A549 cells are associated with a decrease in IRS-1 tyrosine phosphorylation and protein levels. Tissue microarray analysis of human lung carcinoma shows a correlation between IRS-1 protein levels and E-cadherin protein levels. High IRS-1 levels coexist with high E-cadherin levels, whereas low IRS-1 levels coexist with low E-cadherin levels, implying a possibility that IRS-1 protein levels may be linked with EMT. Surprisingly, overexpression of IRS-1 in A549 cells completely blocked TGF-β1–induced EMT and cell migration, inhibited TGF-β1–mediated expression of snail and slug genes, and abolished TGF-β1–mediated repression of E-cadherin promoter activity. In contrast, IRS-1 knockdown by RNAi increased the expression of snail and slug genes and induced EMT. Inhibition of protein tyrosine phosphatase with sodium vanadate, which greatly increased the levels of tyrosine-phosphorylated IRS-1, suppressed TGF-β1–induced actin remodeling and cell morphologic changes. These results show for the first time that TGF-β1 induces EMT through mechanisms involving the modulation of IRS-1 signaling, and that IRS-1 functions as a critical EMT suppressor that suppresses TGF-β1–induced EMT via inhibition of snail and slug expression. [Cancer Res 2009;69(18):7180–7]