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SIPA1 (signal-induced proliferation-associated protein 1) is a GTPase activation protein that can catalyze the hydrolysis of Rap1 bound GTP to GDP. Recently attention has been paid to a potential role for SIPA1 in cancer metastasis; however, the underlying mechanism of how changes in SIPA1 levels may lead to increased metastasis remains poorly understood. In this study, we showed that SIPA1 was mainly localized to the nuclei in highly invasive breast cancer tumor tissue and MDA-MB-231 cells. Knockdown of SIPA1 in MDA-MB-231 altered cell morphology and cell proliferation ability. Furthermore, this study is the first to establish that nuclear SIPA1 can interact with the integrin β1 promoter and activate its transcription; this interaction appears to be important for SIPA1-dependent MDA-MB-231 cell adhesion and invasion. We also demonstrated that the phosphorylation of FAK, Akt and the expression of MMP9, downstream signaling molecules of integrin β1, were decreased upon SIPA1 knockdown, and MDA-MB-231 cell invasion was impaired. Taken together, these results suggest nuclear SIPA1 contributes to breast cancer cell invasion through the regulation of integrin β1 signaling. [ABSTRACT FROM AUTHOR]

Caveolin-1 (Cav-1) plays an important role in modulating cellular signalling, but its role in metastasis is not well defined. A significant reduction in Cav-1 levels was detected in lymph node metastases as compared with primary tumour of head and neck squamous cell carcinoma (HNSCC) specimens (P<0.0001), confirming the downregulation of Cav-1 observed in a highly metastatic M4 cell lines derived from our orthotopic xenograft model. To investigate the function of Cav-1 in metastasis of HNSCC, we compared stable clones of M4 cells carrying human cav-1 cDNA (CavS) with cells expressing an empty vector (EV) in vitro and in the orthotopic xenograft model. Overexpression of Cav-1 suppressed growth of the CavS tumours compared with the EV tumours. The incidence of lung metastases was significantly lower in animals carrying CavS tumours than those with EV tumours (P=0.03). In vitro, CavS cells displayed reduced cell growth, invasion, and increased anoikis compared with EV cells. In CavS cells, Cav-1 formed complex with integrin beta1 and Src. Further application of integrin beta1 neutralising antibody or Src inhibitor PP2 to EV cells illustrated similar phenotypes as CavS cells, suggesting that Cav-1 may play an inhibitory role in tumorigenesis and lung metastasis through regulating integrin beta1- and Src-mediated cell-cell and cell-matrix interactions. [ABSTRACT FROM AUTHOR]