影响食管癌前病变和早期癌光动力学疗效的分子因素与机制研究

项目名称： 影响食管癌前病变和早期癌光动力学疗效的分子因素与机制研究

项目编号： No.30873002

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 汲振余

作者单位： 郑州大学

项目金额： 30万元

中文摘要： 本项目观察了缺氧本项目研究了缺氧诱导因子和凋亡相关基因的表达与PDT疗效的关系，筛选预示PDT疗效的分子指标，以及细胞分化和HIF-1α23545;PDT效应的影响及机制，发现HIF-1α12289;Bax和Survivin蛋白的表达影响了PDT临床疗效，可作为预示食管早期癌患者PDT疗效的分子指标；高分化和经分化诱导后的食管鳞癌细胞对PDT作用敏感性差于低分化食和正常食管上皮细胞；细胞分化状态影响到PpIX的胞内合成和累积水平，光敏剂的细胞内水平不是决定PDT光毒性效能的唯一因素；细胞分化诱导疗法不仅不能增强PDT效应，反而降低疗效，分化诱导对PDT效果的影响部分通过抑制凋亡而实现；光敏剂不同亚细胞定位影响了PDT功效，线粒体的损伤在细胞杀伤过程中起非常重要的作用，是PDT的一个重要靶细胞器；HIF-1α34507;白可抑制PDT对肿瘤细胞的杀伤作用，且部分是通过抑制细胞凋亡而实现，蛋白4.1N的表达缺失与肿瘤转移密切相关， PI3K-C2β36890;过AKT通路在食管鳞癌细胞凋亡的调节过程中起重要作用，以此通路作为靶点有可能是提高食管鳞癌疗效的重要思路。结论对不同肿瘤患者的个体化治疗方案具有重要理论指导意义。

中文关键词： 食管癌;光动力学;光敏剂;细胞分化;细胞凋亡

英文摘要： The relationships between the expressions of HIF-1αnd some apoptosis associated genes in early esophageal cancer and dysplasia before and after PDT and the PDT effects were studied for screening the molecular markers of PDT efficacy. The effects of cell differentiation on the aminolevulinic acid (ALA)-derived endogenous PpIX production and the different subcellular location of photosensitizer on PDT effects and the mechanisms were also investigated in the study. The results showed that the expression of HIF-1?, Bax and Survivin correlates with PDT outcomes and could be prognostic factors of PDT in early esophageal cancer and/or dysplasia. Well differentiated esophageal squamous cancer cells have a higher PpIX production and less sensitivity level than poorly differentiated esophageal squamous cancer cells and esophageal epithelia cells. PpIX cellular level is not the unique determinant to PDT efficiency, cell differentiation may involve in this mechanism. Differentiation treatment could not enhance the clinical PDT efficacy. This attenuated PDT efficacy may be partly due to the resistance to apoptosis. Different subcellular location of photosensitizer may affect the PDT efficacy. Mitochondria are more sensitive and may be important targets for PDT which suggested that future new photosensitizers with mitochondrially-localizing property may be designed for improved PDT effectiveness. Over expression of HIF-1? could attenuate PDT efficacy and may partly due to the inhibition of PDT-induced apoptosis. Decreased expression of 4.1N protein is closely related to cancer metastasis, and PI3K-C2βay a key role in esophageal cancer cell apoptosis via the AKT signaling pathway suggesting that this pathway might be clinically useful. These results about the determinants affecting the sensitivity of individuals to PDT and their mechanisms can further promote the responses of lesions to PDT and improve the survival after clinical cancer treatment through rationalizing therapies in different cases.

英文关键词： esophageal cancer;Photodynamic therapy;photosensitizer;cell differentiation;cell apoptosis