Integrin beta4 regulates SPARC protein to promote invasion

The alpha6beta4 integrin (referred to as beta4 integrin) is a receptor for laminins that promotes carcinoma invasion through its ability to regulate key signaling pathways and cytoskeletal dynamics. An analysis of published Affymetrix GeneChip data to detect downstream effectors involved in beta4-mediated invasion of breast carcinoma cells identified SPARC, or secreted protein acidic and rich in cysteine. This glycoprotein has been shown to play an important role in matrix remodeling and invasion. Our analysis revealed that manipulation of beta4 integrin expression and signaling impacted SPARC expression and that SPARC facilitates beta4-mediated invasion. Expression of beta4 in beta4-deficient cells reduced the expression of a specific microRNA (miR-29a) that targets SPARC and impedes invasion. In cells that express endogenous beta4, miR-29a expression is low and beta4 ligation facilitates the translation of SPARC through a TOR-dependent mechanism. The results obtained in this study demonstrate that beta4 can regulate SPARC expression and that SPARC is an effector of beta4-mediated invasion. They also highlight a potential role for specific miRNAs in executing the functions of integrins