Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8641, Japan.
Cancer Res. 2012 Sep 1;72(17):4459-71. doi: 10.1158/0008-5472.CAN-12-0028. Epub 2012 May 31.
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 chemopreventive drug for HCC, published data about its effects on hepatic mesenchymal cells, such as stellate cells and endothelial cells, remain limited. Using a mouse model in which platelet-derived growth factor (PDGF)-C is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis, steatosis, and eventually, HCC development, we show that peretinoin significantly represses the development of hepatic fibrosis and tumors. Peretinoin inhibited the signaling pathways of fibrogenesis, angiogenesis, and Wnt/β-catenin in Pdgf-c transgenic mice. In vitro, peretinoin repressed the expression of PDGF receptors α/β in primary mouse hepatic stellate cells (HSC), hepatoma cells, fibroblasts, and endothelial cells. Peretinoin also inhibited PDGF-C-activated transformation of HSCs into myofibroblasts. Together, our findings show that PDGF signaling is a target of peretinoin in preventing the development of hepatic fibrosis and HCC.
肝细胞癌 (HCC) 常与肝硬化相关，其高复发率导致患者预后不良。虽然最近的证据表明，无环维甲酸家族成员培他诺滨可能是 HCC 的有效化学预防药物，但关于其对肝间充质细胞（如星状细胞和内皮细胞）的影响的发表数据仍然有限。我们使用一种血小板衍生生长因子 (PDGF)-C 过表达（Pdgf-cTg）的小鼠模型，导致肝纤维化、脂肪变性，最终发展为 HCC，结果表明培他诺滨可显著抑制肝纤维化和肿瘤的发展。培他诺滨抑制了 Pdgf-c 转基因小鼠的纤维化、血管生成和 Wnt/β-catenin 信号通路。在体外，培他诺滨抑制了原代小鼠肝星状细胞 (HSC)、肝癌细胞、成纤维细胞和内皮细胞中 PDGF 受体 α/β 的表达。培他诺滨还抑制了 PDGF-C 激活的 HSCs 向肌成纤维细胞的转化。总之，我们的研究结果表明，PDGF 信号是培他诺滨预防肝纤维化和 HCC 发展的靶点。
