Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development
Menée sur un modèle murin, cette étude montre que la pérétinoine, un rétinoïde acyclique, prévient la survenue d'une fibrose hépatique ou d'un carcinome hépatocellulaire en agissant sur la signalisation du facteur PDGF
Hepatocellular carcinoma (HCC) often develops in association with liver cirrhosis, and its high recurrence rate leads to poor patient prognosis. Although recent evidence suggests that peretinoin, a member of the acyclic retinoid family, may be an effective chemo-preventive drug for HCC, published data regarding its effects on hepatic mesenchymal cells, such as stellate cells and endothelial cells, remain limited. Using a mouse model in which PDGF-C is over expressed (Pdgf-c Tg), resulting in hepatic fibrosis, steatosis, and eventually, HCC development, we demonstrate that peretinoin significantly represses the development of hepatic fibrosis and tumors. Peretinoin inhibited the signaling pathways of fibrogenesis, angiogenesis and Wnt/beta-catenin in Pdgf-c transgenic mice. In vitro, peretinoin repressed the expression of PDGF receptors (PDGFR) alpha/beta in primary mouse hepatic stellate cells (HSCs), hepatoma cells, fibroblasts, and endothelial cells. Peretinoin also inhibited PDGF-C-activated transformation of HSCs into myofibroblasts. Together, our findings demonstrate that PDGF signaling is a target of peretinoin in preventing the development of hepatic fibrosis and HCC.