Periostin在肝细胞癌抗血管生成靶向治疗中的作用及分子机制研究

Periostin (PN) is a recently discovered secreted glycoprotein, which is closely related to tumor angiogenesis, invasion, metastasis and prognosis, but the underlying molecular mechanism is still unclear. Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Theoretically, periostin may become one of the new targets for the anti-angiogenic therapy of HCC. However, so far, there has been less detailed report between periostin and HCC at home and abroad. Recently, we have found that periostin is related with invasion, metastasis and angiogenesis of HCC. Therefore, based on the previous studies, in this project, we aim to: establish hepatoma cell lines with over- or low- expression of periostin under stable transfection and HCC xenografts in nude mice, and use the model to study the biological functions of periostin in HCC tumor growth, metastasis, and angiogenesis; establish a primary SD rat HCC model induced by the chemical carcinogens and investigate the influence of periostin on the anti-cancer effect of vascular inhibitors after blocking its activity by the specific inhibitors; further study the biological functions of periostin in the regulation of HCC cell proliferation, invasion in vitro, and explore its possible molecular mechanisms. In conclusion, this study will explore the effects of periostin on the anti-angiogenic targeted therapy of HCC in vivo and in vitro, and elucidate the underlying molecular mechanisms. Moreover, through this project, we hope to provide a new target for the anti-angiogenic therapy of HCC.

Periostin（PN）是新近发现的一种分泌性糖蛋白，与肿瘤血管生成、侵袭转移和预后等密切相关，但分子机制尚不清楚。肝细胞癌（简称肝癌）是典型的多血管性肿瘤，理论上而言，PN可成为肝癌抗血管治疗的新靶点之一。但迄今国内外针对PN在肝癌中的研究较少。我们近期研究发现，PN与肝癌侵袭转移及肿瘤血管生成相关。因此，本项目拟在前期研究基础上，通过：建立PN过表达或低表达稳转的肝癌细胞系与肝癌裸鼠移植瘤模型，研究PN在肿瘤生长、侵袭、转移以及血管生成中的作用；建立诱导性SD大鼠肝癌模型，探讨特异性阻断PN的活性对血管抑制剂抗癌效应的影响；体外进一步研究PN对肝癌细胞增殖、侵袭等生物学行为的调控作用，并探讨其可能的分子机制。从体内和体外两个层面探索PN在肝癌发生发展、抗血管靶向治疗中的作用及其相关的分子机制，为抗血管生成治疗肝癌提供新靶点。

Periostin（POSTN或PN）是新近发现的一种分泌性糖蛋白，与肿瘤血管生成、侵袭转移和预后等密切相关，但分子机制尚不清楚。肝细胞癌（简称肝癌）是典型的多血管性肿瘤，理论上而言，POSTN可成为肝癌抗血管治疗的新靶点之一。但迄今国内外针对POSTN在肝癌中的研究较少。近期，课题组收集71份人肝癌和癌旁石蜡标本与临床资料，采用免疫组织化学方法检测证实，POSTN在肝癌组织中存在差异表达，其阳性率为73.2%（52/71），明显高于癌旁组织中的19.7%（14/71）。进一步结合相应的临床病理资料统计分析后发现，POSTN表达阳性率与肿瘤结节数（P=0.07）、微血管侵犯（P=0.013）、Edmondson分级（P=0.003）、肿瘤包膜的完整性（P=0.038）和TNM分期（P=0.000）有关；与阴性组相比，POSTN阳性表达组中VEGF和微血管密度（MVD）水平更高（P均=0.000）；采用Kaplan-Meier法对POSTN阳性组和阴性组的总生存率和无病生存率进行分析，发现两组的总生存率和无病生存率均有显著差异，阳性组生存率明显低于阴性组（P均<0.001）；应用Cox风险回归模型多因素分析发现，POSTN表达、血管侵犯、肿瘤大小、Edmondson分级、肿瘤包膜的完整性和TNM分期是影响肝癌患者总生存和无病生存的独立危险因素。上述结果表明：POSTN高表达与肝癌的转移潜能及患者预后不佳密切相关。随后，我们建立POSTN过表达稳转的肝癌细胞系，研究POSTN在肿瘤生长、侵袭、转移以及血管生成中的作用，同时采用生物信息学分析筛选出下游关键基因，并进行验证，结果发现，POSTN在肝癌细胞中通过调控RAP1A、DDIT3、THBS1、CBL基因的表达在肝癌方向上发挥作用，为寻找肝癌治疗新靶点提供思路。