Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma

Background&Aims: Human hepatocellular carcinorna (HCC) can invade the portal vein and metastasize to other parts of the liver. Currently, the molecular and cellular mechanisms underlying intrahepatic metastasis of HCC are poorly understood. Tumor invasiveness could be considered an aspect of dysregulated motility, and the mechanisms that inhibit cell movement are considered to counteract the spreading of cancer cells through the liver. Accumulating observations suggest that the CD81 tetraspanin may have-an inhibitory effect on cell movement. Methods: In the present study using both loss-and gain-of-gerie function approaches, we verified that the functional interaction of tetraspanin CD81 with type 11 phosphoinositide 4-kinase (Pl4KII) suppressed HCC cell motility by promoting the formation of CD81-enriched vesicles, non-endosomal intracellular structures, that sequestered actinin-4 with consequent remodeling of actin cytoskeleton. Results: We reported that HCC cells expressing CD81 showed an inability to metastasize compared with HCC cells with undetectable levels of CD81. Conclusions: Taken together, these findings indicate that CD81 functions as a molecular organizer of membrane microdomains, whereby proteins such as P14KII control actin remodeling and cell motility, establishing a role for these genes as negative modifiers of oncogenicity and HCC progression.