Based on the combination co-immunoprecipitation (Co-IP) with two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS), our results revealed that CD151 played the crucial role in the progression of HCC through formation of tetraspanin CD151 network with molecular partners, such as Mortalin, integrins α6β1 and c-Met 9. This evidence concerns the gene CD151 and hepatocellular carcinoma.