PARVA promotes metastasis by modulating ILK signalling pathway in lung adenocarcinoma

Abstract

α-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony-forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation in vitro. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in in vivo mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3β. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3β. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression.