Periostin基于EGFR信号通路调控食管鳞癌血管生成和靶向治疗的作用及机制研究

Squamous cell carcinoma is the most common histologic type of the primary esophageal cancer in our country, which is characterized by postoperative invasion and metastasis, poor prognosis and short survival. Angiogenesis plays an important role in promoting the process of invasion and metastasis of esophageal squamous cell carcinoma (ESCC). Recent studies found that periostin (PN), as a secreted glycoprotein, was closely related to the angiogenesis in a variety of malignancies. Theoretically, PN may become one of the new targets for the anti-angiogenic therapy of ESCC. But so far, there has been less detailed report between periostin and ESCC at home and abroda. Our research group recently discovered that the expression levels of periostin, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor were positively correlated in ESCC. Therefore, based on the previous studies, in this project, we aim to: construct ESCC cell lines with over- or low- expression of periostin under stable transfection and ESCC xenografts in nude mice, and use the model to analyze the biological functions of periostin in ESCC tumor growth, metastasis and angiogenesis based on EGFR signaling pathway; establish a primary SD rat ESCC model induced by the chemical carcinogens and investigate the influence on the targeted threpay of ESCC by inhibition of periostin combined with EGFR-targeted drugs; and validate these key indicators in clinical specimens. In conclusion, this study will explore the effects of periostin on the anti-angiogenic targeted therapy of ESCC in vivo and in vitro based on the EGFR signaling pathway, and elucidate the underlying molecular mechanisms. Moreover, by performing this project, we hope to provide a new potential target and new strategies for the treatment of ESCC in clinic.

鳞癌是我国原发性食管癌中最常见组织学类型，具有术后易侵袭转移、生存期短及预后差等特点。肿瘤血管生成在食管鳞癌侵袭转移过程中发挥了重要促进作用。近期发现periostin（PN）与多种恶性肿瘤血管生成密切相关，理论上而言，PN可有望成为食管鳞癌抗血管治疗新靶点之一，但迄今国内外对此研究较少。课题组近期发现，食管鳞癌中PN与EGFR、血管生成因子呈正相关表达。因此，本项目拟在前期研究基础上，通过：构建PN过表达或低表达稳转食管鳞癌细胞系与裸鼠移植瘤模型，解析基于EGFR信号通路PN在食管鳞癌生长、转移及血管生成中的作用和机制；建立靶向干预动物模型探索EGFR靶向药联合抑制PN对食管鳞癌生长、转移及血管生成作用及机制；并在临床标本中验证上述关键指标。从体内和体外两个层面探索基于EGFR信号通路PN在食管鳞癌发生发展、血管生成和靶向治疗中的作用及分子机制，为临床治疗食管鳞癌提供潜在新靶点和新策略。

鳞癌是我国原发性食管癌中最常见组织学类型，具有术后易侵袭转移、生存期短及预后差等特点。肿瘤血管生成在食管鳞癌侵袭转移过程中发挥了重要促进作用。近期发现periostin（POSTN或PN）与多种恶性肿瘤血管生成密切相关，理论上而言，POSTN可有望成为食管鳞癌抗血管治疗新靶点之一，但迄今国内外对此研究较少。课题组在本项目中通过：（1）结合生物信息学和免疫组化验证的方法，证实POSTN与EGFR信号通路中的关键分子PI3K等存在共表达关系，同时也与血管生成及EMT相关分子等存在一定的共表达关系，而且上述分子的差异表达水平患者其生存预后存在明显差异，可作为预测食管鳞癌患者预后的独立预测因子；（2）采用RNA干扰技术敲低食管鳞癌细胞株ECa-109中的POSTN基因表达，利用基因表达谱芯片进行差异基因的筛选，同时利用IPA软件对差异基因进行信号通路的富集，为分子机制的探索奠定了基础；（3）其它研究：发现FN和LN与食管鳞癌的EMT水平密切相关，同时上述分子的表达水平亦对患者的预后具有独立预测作用。本项目从体内和体外两个层面探索基于EGFR信号通路PN在食管鳞癌发生发展、血管生成和靶向治疗中的作用及分子机制，为临床治疗食管鳞癌提供潜在新靶点和新策略。