Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma.
OBJECTIVE
Human hepatocellular carcinoma (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-gene function approaches, we verified that the functional interaction of tetraspanin CD81 with type II phosphoinositide 4-kinase (PI4KII) 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 PI4KII control actin remodeling and cell motility, establishing a role for these genes as negative modifiers of oncogenicity and HCC progression.
Mazzocca
Antonio
A
Department of Internal Medicine, Center for Research, Transfer and High Education, DENOthe, University of Florence, Florence, Italy. antonio.mazzocca@vanderbilt.edu
Liotta
Francesco
F
Carloni
Vinicio
V
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism; D000185:Actinin / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology* / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D060225:Tetraspanin 28; D014162:Transfection
C111453:ACTN4 protein, human; D015703:Antigens, CD; C554798:CD81 protein, human; D060225:Tetraspanin 28; D000185:Actinin; D049452:Green Fluorescent Proteins; D019870:1-Phosphatidylinositol 4-Kinase