Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Hepatol Res. 2014 Jan;44(1):22-30. doi: 10.1111/hepr.12166. Epub 2013 Jun 20.
Osteopontin (OPN) is a multifunctional protein, involved in pathological conditions including inflammation, immunity, angiogenesis, fibrosis and cancer progression in various tissues. Hepatic inflammation and fibrosis induced by feeding with a diet deficient in methionine and choline (MCD diet) were markedly attenuated in OPN knockout mice when compared with wild-type mice in the model of non-alcoholic steatohepatitis (NASH). Hepatic cholangiocytes, myofibroblastic stellate cells and natural killer T cells were suggested to secret OPN in mice fed an MCD diet. Plasma and hepatic OPN levels were significantly higher in patients with NASH with advanced fibrosis than in those with early fibrosis. Hepatic OPN mRNA level was correlated with hepatic neutrophil infiltration and fibrosis in patients with alcoholic liver diseases. In those with hepatocellular carcinoma (HCC), OPN levels in plasma and HCC were prognostic factors after liver resection or transplantation. Downregulation of OPN inhibited tumor growth and lung metastasis in nude mice implanted with HCC cells. The single nucleotide polymorphism in the promoter region of the OPN gene was shown to be associated with activity of hepatitis in chronic hepatitis C patients, prognosis in patients with HCC, and growth and lung metastasis of HCC xenografts in nude mice. OPN was reported to be a downstream effecter of Hedgehog pathway, which modulates hepatic fibrosis and carcinogenesis. This review focuses on the roles of OPN in hepatic inflammation, fibrosis and cancer progression. Further elucidation of cellular interactions and molecular mechanisms associated with OPN actions may contribute to development of novel strategies for treatment of the liver diseases.
骨桥蛋白 (OPN) 是一种多功能蛋白，参与多种病理状态，包括炎症、免疫、血管生成、纤维化和癌症进展，涉及多种组织。与野生型小鼠相比，在非酒精性脂肪性肝炎 (NASH) 模型中，缺乏蛋氨酸和胆碱的饮食喂养引起的 OPN 基因敲除小鼠的肝炎症和纤维化明显减轻。在 MCD 饮食喂养的小鼠中，肝胆小管细胞、肌纤维母细胞样星状细胞和自然杀伤 T 细胞被认为分泌 OPN。与早期纤维化患者相比，NASH 伴晚期纤维化患者的血浆和肝 OPN 水平显著升高。酒精性肝病患者的肝 OPN mRNA 水平与肝中性粒细胞浸润和纤维化相关。在肝细胞癌 (HCC) 患者中，血浆和 HCC 中的 OPN 水平是肝切除或移植后患者的预后因素。下调 OPN 抑制了裸鼠植入 HCC 细胞后的肿瘤生长和肺转移。OPN 基因启动子区域的单核苷酸多态性与慢性丙型肝炎患者的肝炎活动、HCC 患者的预后以及裸鼠 HCC 异种移植物的生长和肺转移相关。据报道，OPN 是 Hedgehog 通路的下游效应因子，调节肝纤维化和癌变。本综述重点介绍 OPN 在肝炎症、纤维化和癌症进展中的作用。进一步阐明与 OPN 作用相关的细胞相互作用和分子机制可能有助于开发治疗肝脏疾病的新策略。
