[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by beta-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.
International Journal of Cancer 08/2009; 126(5):1095-108. DOI:10.1002/ijc.24800 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influence of HFE gene mutations and liver iron overload on hepatocellular carcinoma (HCC) occurrence in patients with cirrhosis is subjected to controversial results. The aim of this work was to clarify this influence in a large cohort of prospectively followed-up cirrhotic patients classified according to the cause of their liver disease.
Three hundred one consecutive cirrhotic patients (162 alcoholics and 139 HCV-infected patients) were included at time of diagnosis of cirrhosis and followed-up. Liver iron overload on initial biopsy according to modified Deugnier's score and C282Y/H63D HFE gene mutations were assessed.
In patients with alcoholic cirrhosis (mean iron score, 2.0 +/- 3.0; mean time of follow-up, 66.1 +/- 45.1 months), 40 (24.6%) developed HCC. Thirteen (8.02%) were heterozygotes for C282Y HFE gene mutation and had higher hepatic iron scores (3.6 +/- 3.8 vs 1.9 +/- 2.8, respectively, P = .05). In univariate analysis, liver iron overload as a continuous variable (HR, 1.23 [1.13-1.34], P < .001) or in binary coding with an optimal threshold of iron score >/=2.0 (HR, 4.1 [2.1-7.3], P < .0001) and C282Y mutation carriage (HR, 2.7 [1.2-6.3], P = .01) were risk factors for HCC. In multivariate analysis, liver iron and C282Y mutation carriage remained independent risk factors for HCC. In patients with HCV-related cirrhosis (C282Y mutation carriage, 17 [12.23%]; mean liver iron score, 0.9 +/- 1.9; mean time of follow-up, 85.5 +/- 42.1 months; HCC, 63 [45.32%] patients), C282Y mutation carriage and liver iron were not associated with HCC occurrence.
Liver iron overload and C282Y mutation are associated with a higher risk of HCC in patients with alcoholic but not HCV-related cirrhosis.