青藤碱预防肝癌发生的作用及其机制探索

How to efficiently prevent hepatocarcinoma is a tough clinical problem all over the world. It has been known that hepatocarcinoma is a inflammation-associated cancer, and that the course of hepatocarcinogenesis and development attributes to the over-activation/over-expression of CYP1A2, Ras and its down-streaming signal pathways and molecules including COX-2, iNOS, inflammatory factors and ROS. The pharmacologic actions of sinomenine (SIN) include the anti-inflammation and immuno-depression (to inhibit the proliferation and activation of inflammatory cell and the release of inflammatory factors) and the anti-oxidation (to remove ROS). SIN has been applied to cure arthritis in clinic and it has better therapeutic effect and safety than non-steroidal anti-inflammatory drugs. It has been indicated in our previous studies that C/EBPβand p-STAT3, which are the key down-streaming transcription factors of Ras, and COX-2 were over-expressed in both human and DEN-induced rat hepatocarcinoma. Moreover, we found that SIN inhibited cell growth and induced cell apoptosis in hepatocarcinoma cells, probably by the export from nuclei of NF-κB. Is it possible for SIN to prevent and cure hepatocarcinoma via its activation of anti-inflammation, immune-depression and anti-oxidation? In this project, we plan to investigate its in vitro effects of protecting hepatic cells and inhibiting activation/growth of macrophages and hepatocarcinoma cells, and its in vivo prevention and cure effects on hepatocarcinoma. Furthermore, the further molecular mechanisms will be studied, too. There is a hope to provide a novel proposal to prevent hepatocarcinoma after the fulfillment of this project.

预防肝癌发生是世界性临床难题。肝癌是一种炎症相关性肿瘤，HBV和DEN等因素诱导CYP1A2、Ras信号通路及其下游分子COX-2、iNOS、炎症因子和ROS的激活/表达，是肝癌发生发展的机制。青藤碱（SIN）具有抗炎和抑制免疫及抗氧化作用，临床用于治疗关节炎，其疗效和安全性均优于非甾体类抗炎药。我们前期研究发现：Ras下游关键转录因子C/EBPβ和p-STAT3以及COX-2在人和DEN诱导的大鼠肝癌组织中均过表达；SIN能够在体内外抑制肝癌细胞生长、诱导凋亡、提高化疗敏感性。那么，SIN能否通过抗炎、抑制免疫和抗氧化作用预防肝癌发生？本项目拟在体外验证SIN保护肝细胞、抑制巨噬细胞和肝癌细胞激活/生长的作用，同时拟借助DEN诱导大鼠肝癌模型和裸鼠皮下种植瘤模型在体内验证SIN能否预防肝癌发生，并探讨其分子机制。该研究有望为预防肝癌发生提供新方案。

肝癌是最常见的恶性肿瘤之一，预防肝癌发生是世界性临床难题。研究表明肝癌是一种炎症相关性肿瘤，HBV等各种致癌因素可诱导激活炎症及各种信号通路，是肝癌发生发展的机制之一。中药提取单体盐酸青藤碱具有抗炎和抑制免疫作用，临床用于治疗关节炎，其疗效和安全性均优于非甾体类抗炎药。本项目旨在探讨盐酸青藤碱对肝癌的防治作用及其机制。首先，我们的研究结果表明，盐酸青藤碱抑制肝癌细胞生长的分子机制为：下调肝癌细胞中p-GSK3β、p-mTOR、p-STAT3、p-Akt、Slug、Twist分子水平，上调IκB、EPLIN、FOXO3a分子表达水平，促进NF-κB出细胞核。此外，我们也证实盐酸青藤碱可下调炎症因子IL-6和TNF-α所诱导的p-GSK3β、p-STAT3、Slug表达水平升高；在大鼠体内证实盐酸青藤碱对DEN诱导的大鼠肝癌模型的防治作用，其可下调炎症相关基因COX-2表达水平。该研究为将来可能将盐酸青藤碱用于临床提供基础理论依据。