Here, we have demonstrated that CD147 is a bona fide signaling receptor for extracellular Cu2+ in cancer cells: the self-association of CD147 mediated by extracellular Cu2+ signals the up-regulation of MMP-2 and MMP-14 in HCC cells through activating PI3K/Akt pathway, stimulates MMP-2 production from neighboring fibroblasts and promotes HCC cell invasion. Here, MMP14 is linked to hepatocellular carcinoma.