Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.
BACKGROUND
Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling.


RESULTS
We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses.


CONCLUSIONS
Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.
Battaglia
Serena
S
Inserm, Unité 785, Villejuif, France.
Benzoubir
Nassima
N
Nobilet
Soizic
S
Charneau
Pierre
P
Samuel
Didier
D
Zignego
Anna Linda
AL
Atfi
Azeddine
A
Bréchot
Christian
C
Bourgeade
Marie-Françoise
MF
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology* / Q000821:virology*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014758:Viral Core Proteins / Q000378:metabolism*
D050505:Mutant Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus