期刊
JOURNAL OF CELL SCIENCE
卷 120, 期 12, 页码 2053-2065出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.03460
关键词
connective tissue growth factor; breast cancer; ERK1/2; integrin; S100A4; cell migration; F-actin
类别
Connective tissue growth factor ( CTGF) expression is elevated in advanced stages of breast cancer, but the regulatory role of CTGF in invasive breast cancer cell phenotypes is unclear. Presently, overexpression of CTGF in MCF-7 cells (MCF-7/CTGF cells) enhanced cellular migratory ability and spindle-like morphological alterations, as evidenced by actin polymerization and focal-adhesion-complex aggregation. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) impaired cellular migration and promoted a change to an epithelial-like morphology. A neutralizing antibody against integrin alpha v beta 3 significantly attenuated CTGF-mediated ERK1/2 activation and cellular migration, indicating that the integrin-alpha v beta 3-ERK1/2 signaling pathway is crucial in mediating CTGF function. Moreover, the cDNA microarray analysis revealed CTGF-mediated regulation of the prometastatic gene S100A4. Transfection of MCF-7/CTGF cells with ASS100A4 reversed the CTGF-induced cellular migratory ability, whereas overexpression of S100A4 in MDA231/AS cells restored their high migratory ability. Genetic and pharmacological manipulations suggested that the CTGF-mediated S100A4 upregulation was dependent on ERK1/2 activation, with expression levels of CTGF and S100A4 being closely correlated with human breast tumors. We conclude that CTGF plays a crucial role in migratory/invasive processes in human breast cancer by a mechanism involving activation of the integrin-alpha v beta 3-ERK1/2-S100A4 pathway.
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