eIF3a及其遗传多态对鼻咽癌放疗反应的影响与分子机制研究

Genetic variation is one of the main factors which affect individual difference for nasopharyngeal carcinoma radiotherapy reaction. Our previous study found that eIF3a and its genetic polymorphisms was related to the radiotherapy sensitivity of nasopharyngeal carcinoma. And we also identified that eIF3a can regulate several genes expression in BER DNA repair pathways. Therefore, we proposed that eIF3a and its polymorphisms affected nasopharyngeal carcinoma radiotherapy reaction, through changing BER DNA repair pathway expression level and activity. In the present study, we will first identify if eIF3a and its genetic polymorphisms affect nasopharyngeal carcinoma radiotherapy reaction in a large sample size patients. Secondly, we will employ real-time PCR, western blotting and single cell electrophoresis assay to identify if eIF3a and its genetic polymorphisms regulate BER DNA repair pathway expression level and activity. At last, dual luciferase reporter, bioinformatics, vitro transcription, prokaryotic expression, protein purification and EMSA will be performed to explore how eIF3a and its genetic polymorphisms regulate BER DNA repair pathway. This study will not only find the probably genetic molecular markers for nasopharyngeal carcinoma radiotherapy individual differences, but also unveil a new mechanism in regulation of BER DNA repair pathways in radiation injury.

遗传变异是鼻咽癌放疗反应个体差异的主要因素之一。我们前期研究表明eIF3a 及其多态与鼻咽癌放射敏感性相关，并发现 eIF3a 能够影响部分与放射损伤相关的 BER DNA修复途径基因表达。因此，我们推测eIF3a 及其遗传多态能影响鼻咽癌放疗反应，其机制可能是eIF3a 及其多态调控BER DNA修复途径。本研究将首先通过大样本临床实验证实 eIF3a 及其多态是否能影响鼻咽癌放疗反应。然后使用Real-time PCR、 Western Blotting、单细胞凝胶电泳明确 eIF3a 及其多态对BER DNA 通路表达及活性的影响。最后使用荧光素酶报告基因、体外转录、原核表达和 EMSA 探索 eIF3a及其多态对该途径调控的具体分子机制。本课题不仅为鼻咽癌放疗反应个体差异提供可能的遗传分子标志物，还将为调控 BER DNA修复途径提供一种新的机制，对鼻咽癌个体化治疗具有重要意义。

本项目研究遗传多态性（eIF3a、Wnt/β-catenin 信号通路以及内质网信号通路等相关基因）对鼻咽癌放疗反应的影响。研究发现：1. eIF3a rs3808952与放射性皮炎相关，而eIF3a rs3824830与放疗反应相关。2. CTNNB1 rs1880481、 rs3864004、GSK3β rs3755557 多态性与放疗治疗效果相关，而GSK3β rs375557、APC rs454886 多态性与放疗毒性（皮炎、口腔黏膜反应）相关。3. CANX rs7566、CALCR rs2528521多态性与放化疗治疗效果相关，而VCP rs2074549 多态性与放化疗引起的骨髓相关。