Caveolin-1 promotes hepatocellular carcinoma tumourigenesis, migration and invasion via Met-ERK1/2 pathway

Conference Theme: Systems Biology Approaches to Cancer and Metabolic DiseaseBACKGROUND AND AIMS: Caveolin-1 (Cav1), the major scaffold protein of caveolae and a key component at focal adhesions has been implicated in hepatocarcinogenesis; nonetheless, the underlying mechanisms remain poorly defined. In this study, we aimed to functionally characterize Cav1 in hepatocellular carcinoma (HCC) and dissect the role of Cav1 in hepatocyte growth factor (HGF)-Met signaling pathway. METHODS: Cav1 expression was examined in human HCC tissues by immunohistochemistry. Cav1 overexpressing and knockdown stable clones were established in HCC cells and subjected to functional characterization. Activity and expression of Met were manipulated in order to corroborate the regulation of HGF-Met axis by Cav1. RESULTS: Cav1 was not detected in all non-tumourous tissues but progressively increased in expression in primary and metastatic tumours. Cav1 overexpression correlated significantly with venous invasion. Overexpressing Cav1 in HCC cells promoted in vitro cell growth, motility and invasiveness, as well as in vivo tumourigenecity. Cav1 overexpression upregulated Met expression and sensitized the cells to HGF stimulation while depletion of Met expression and activity suppressed HGF-induced cell migration and invasion. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation was involved in the Cav1-mediated Met transactivation. Conversely, knockdown of Cav1 substantially reduced HGF-induced motility and invasiveness of metastatic HCC cells. CONCLUSION: Our study demonstrated the clinical significance and positive regulation of Cav1 in HCC tumourigenesis and invasiveness. This is the first report showing the upregulation of Met by Cav1 and that Cav1 is a pivotal mediator in HGFMet signaling.Days of Molecular Medicine 2010: Systems Biology Approaches to Cancer and Metabolic Disease, Stockholm, Sweden, 20-22 May 2010. In the Program of the Days of Molecular Medicine 2010, 2010, p. 62, abstract no. 7