In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 18 ( 2009-09-15), p. 7180-7187
Abstract:
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]
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-08-4470
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink