Abstract
Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.
Highlights
Liver carcinogenesis related to metabolic syndrome (MS) is becoming a major challenge with the increase in overweight patients and type 2 diabetes worldwide [1, 2]
fatty acid-binding protein 4 (FABP4) expression evaluated by western blotting was significantly higher in hepatocellular carcinoma (HCC) from patients with MS without metformin compared to MS patients with metformin or other risk factors, including chronic alcohol consumption or HCV and HBV infection (p < 0.0001) (Fig. 1a)
Representative cases of FABP4 immunostaining in HCC illustrated in Fig. 2 shows that FABP4 was predominantly found in sinusoidal cells of HCC/MS without metformin, while few vascular channels within the portal tracts and fibrous bands were labelled in non-tumoral livers
Summary
The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4)
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