HCV core-mediated activation of latent TGF-β via thrombospondin drives the crosstalk between hepatocytes and stromal environment.
OBJECTIVE
The mechanisms by which fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) develop during chronic hepatitis C virus (HCV) infection are not fully understood. We previously observed that HCV core protein induced a TGF-β-dependent epithelial mesenchymal transition, a process contributing to the promotion of cell invasion and metastasis by impacting TGF-β1 signalling. Here we investigated HCV core capacity to drive increased expression of the active form of TGF-β1n transgenic mice and hepatoma cell lines.


METHODS
We used an in vivo model of HCV core expressing transgenic mice.


RESULTS
We observed that about 50% of genes deregulated by core protein expression were TGF-β1 target genes. Active TGF-β levels were increased in HCV core transgenic mouse livers. Overexpression of core protein in hepatoma cells increased active TGF-β levels in culture supernatants and induced Smad2/3 phosphorylation, thus reflecting activation of the TGF-β signaling pathway. Moreover, our data showed the implication of thrombospondin-1 in core-dependent TGF-β activation. Finally, hepatoma cells expressing HCV core could activate stellate cells in co-culture and this activation was TGF-β dependent.


CONCLUSIONS
Collectively, these data delineate a novel paradigm where HCV may be related to liver pathogenesis through its ability to induce a local, intrahepatic TGF-β activation. They argue for a dual impact of HCV core on liver fibrosis and liver carcinogenesis: HCV core could act both as autocrine and paracrine factor modulating TGF-β responses within hepatocytes and in stromal environment through TGF-β activation.
INSERM U785, Villejuif F-94800, France; Univ Paris-Sud, UMR-S 785, Villejuif F-94800, France.
Nassima
N
Benzoubir
Charlène
C
Lejamtel
Serena
S
Battaglia
Barbara
B
Testoni
Barbara
B
Benassi
Claire
C
Gondeau
Laure
L
Perrin-Cocon
Christophe
C
Desterke
Valérie
V
Thiers
Didier
D
Samuel
Massimo
M
Levrero
Christian
C
Bréchot
Marie-Françoise
MF
Bourgeade
D000818:Animals; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019700:Thrombospondin 1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta
Active TGF-beta; ECM; EMT; HCC; HCV; HCV core; HCV core from non-tumor nodule; HCV core from tumor nodule; HSC; Paracrine effect; SMA; Stellate cell activation; TGF-β; TSP; cNT; cT; epithelial mesenchymal transition; extracellular matrix; hepatic stellate cell; hepatitis C virus; hepatocellular carcinoma; smooth muscle actin; transforming growth factor beta; trombospondin