Integrin ?9?1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition.

ABSTRACT: The integrin ?9?1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that ?9?1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As ?9?1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that ?9?1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that ?9?1 forms a tri-partite protein complex with ?-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and ?-catenin phosphorylation. These findings were consistent in cells in which: ?9?1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing ?9?1. These in vitro results are biologically significant as ?9?1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without ?9?1 expression or when integrin expression is suppressed. Furthermore, integrin ?9?1 is expressed in primary human small cell lung cancer and patients having a high expression of ?9?1 demonstrated significantly worse long-term survival compared with patients with low ?9?1 expression. These findings highlight a novel mechanism of integrin ?9?1 function in human cancer.

SUBMITTER: Gupta SK 

PROVIDER: S-EPMC3368989 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature