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Aim: Caveolin-1 and flotillin-1 are considered markers of lipid rafts and involve in signal transduction.However, the roles of caveolin-1 and flotillin-1 in development and progression of cancer remain largely unknown.The present study was aimed to investigate the mechanisms and clinical prognostic significance of lipid rafts in hepatocellular carcinoma (HCC).Methods: Western blotting analyses was applied to examine caveolin-1 and flotillin-1 expression and raft-associated Akt signaling pathway involved in the regulation of cell survival in 90 human HCC and adjacent non-cancerous liver tissues (ANT) samples.Immunohistochemistry (IHC) was performed to examine caveolin-1 and flotillin-1 protein expression in paraffin-embedded tissues from 90 HCC patients.Statistical analyses were applied to evaluate the diagnostic value and associations of caveolin-1 and flotillin-1 expression with clinical parameters.Results: Significant caveolin-1 and flotillin-1 over-expression was found in HCC tissues compared to ANT, and were confirmed by IHC and western blotting.Raft-associated Akt signaling pathway involved in the regulation of cell survival was altered by western blotting in HCC microdomain-enriched subcellular fractions purified from paired HCC and ANT samples.Patients with higher caveolin-1 and flotillin-1 expression had shorter overall survival time, whereas those with lower caveolin-1 and flotillin-1 expression had longer survival time.Conclusions: We showed that caveolin-1 and flotillin-1 are associated with aggressive characteristics of HCC, and suggested the possibility as the prognostic markers in patients with HCC.Our results also demonstrated that only the raft-associate Akt but not total plasma Akt determines the activity and direction of its signalling pathway.This underlines the importance of focusing on membrane microdomains instead of the global cellular membrane when the functions of signaling proteins are studied.Our results are the first to clearly demonstrate that cells can be differentially targeted according to differences in the structures of their membrane microdomains.