内质网蛋白ERp29抑制PERK和/或IRE-1信号通路导致鼻咽癌放疗抵抗的机制研究

ERp29, an endoplasmic reticulum protein, was found up-regulated in radiation resistant nasopharyngeal carcinoma by comparative proteomics study. However, the function and molecular mechanism of ERp29 are still unclear. Further studies showed that ERp29 could significantly enhance the radiation resistance in nasopharyngeal carcinoma cells and inhibit activity of the endoplasmic reticulum trans-membrane protein PERK and IRE-1. On this premise, the project intends to use the methods of gene transfection, RNA interference, quantitative PCR, Western blotting, kinase activity assay and the nude mice model to analysis if ERp29 inhibits the activity of PERK and / or IRE-1 signal pathway and their corresponding target genes in nasopharyngeal carcinoma, which causes the result of enhancing proliferation and attenuating apoptosis and autophagy and eventually inducing radiotherapy resistance. The project not only contributes to reveal the function and molecular mechanism of ERp29 in nasopharyngeal carcinoma radiotherapy resistance, but also provides the scientific evidence for predicting radiosensitivity and targeting therapy in nasopharyngeal carcinoma.

前期比较蛋白质组学研究发现，内质网应激蛋白ERp29在放疗抵抗的鼻咽癌组织中表达上调，但其功能及机制不清楚。进一步研究发现ERp29能明显增强鼻咽癌细胞的放疗抵抗性，并能抑制内质网应激感受跨膜蛋白PERK及IRE-1的活化。在此基础上，本项目拟采用基因转染、RNA干扰、定量PCR、免疫印迹、体外激酶活性实验、裸鼠移植瘤模型等方法从分子、细胞、动物模型水平分析和证实鼻咽癌中ERp29表达上调导致PERK和/或IRE-1信号通路传导及相应靶基因活性受抑制，进而增强了鼻咽癌细胞的生长增殖、抗凋亡和抗自噬能力，最终导致鼻咽癌放疗抵抗。项目研究不仅有助于揭示ERp29表达上调在鼻咽癌细胞放疗抵抗性中的作用及其机制，而且能为鼻咽癌的放疗敏感性预测以及鼻咽癌的靶向治疗和个体化放疗提供科学依据。

前期比较蛋白质组学研究发现，内质网应激蛋白ERp29在放疗抵抗的鼻咽癌组织中表达上调，但其功能及机制不清楚。前期研究发现ERp29能明显增强鼻咽癌细胞的放疗抵抗性，并能抑制内质网应激感受跨膜蛋白PERK及IRE-1的活化。本项目证实了ERp29分别通过抑制PERK/elF2α、IRE-1/ XBP-1内质网应激信号通路的激活进而抑制核因子CHOP及JNK的表达，进而增强了鼻咽癌细胞的生长增殖、抗凋亡和抗自噬能力，最终导致鼻咽癌放疗抵抗。项目研究不仅有助于揭示ERp29表达上调在鼻咽癌细胞放疗抵抗性中的作用及其机制，而且能为鼻咽癌的放疗敏感性预测以及鼻咽癌的靶向治疗和个体化放疗提供科学依据。