RESUMO
Integrin α3ß1 is expressed on many types of cancer cells and can regulate tumor growth and progression. In the present study, we examined the roles and molecular mechanism of integrin α3ß1 in modulating cell proliferation and migration of p53-deficient non-small cell lung cancer (NSCLC) cells. Reduced expression of integrin α3 by RNA silencing clearly induces cell proliferation and migration in H1299 cells, compared with those in control cells. Enhanced proliferation in integrin α3-silenced cells is mediated by upregulation and nuclear localization of cyclin-dependent kinases, and these effects require the activation of Akt and ERK as evidenced by treatment with LY294002 and PD98059, respectively. Furthermore, suppression of integrin α3 expression induces the expression of nuclear factor-κB and Bcl-2 as well as epidermal growth factor receptor, which are positively correlated with cell proliferation and survival. In contrast, increase in cell migration of integrin α3-silenced cells is found to be independent of Akt or ERK signaling pathways. Collectively, these findings suggest that integrin α3ß1 plays pivotal roles in regulating cell proliferation and migration that enhance the invasive type of p53-deficient NSCLC cells.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Movimento Celular/genética , Proliferação de Células , Integrina alfa3beta1/genética , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quinases Ciclina-Dependentes , Receptores ErbB/metabolismo , Humanos , Integrina alfa3beta1/metabolismo , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Transfecção , Proteína Supressora de Tumor p53/deficiência , Regulação para CimaRESUMO
We have previously reported that tissue inhibitor of metalloproteinases-2 (TIMP-2), an endogenous inhibitor of matrix metalloproteinase, modulates angiogenic responses through the MMP inhibition-independent activity. In this study, we investigate the molecular mechanisms of TIMP-2-mediated growth inhibition in response to fibroblast growth factor-2 (FGF-2). Pre-treatment with a protein tyrosine phosphatase inhibitor orthovanadate or expression of a dominant negative Shp-1 mutant fails to induce TIMP-2 inactivation of FGF-2 signaling pathways in human microvascular endothelial cells. We also show that TIMP-2 inhibition of FGF-2-induced p42/44(MAPK) activation and cell proliferation is associated with TIMP-2 binding to integrin alpha3beta1 on endothelial cell surfaces, as demonstrated by use of anti-integrin alpha3 or beta1 blocking antibodies, or disruption of integrin alpha3 expression by siRNA. Collectively, our results indicate that TIMP-2 inhibits FGF-2 signaling pathways through association with integrin alpha3beta1 and Shp-1-dependent inhibition of p42/44(MAPK) signaling, which in turn, results in suppression of FGF-2-stimulated endothelial cell mitogenesis.