疗效差异基因BRCC3和RPA3介导DNA损伤修复在鼻咽癌放射抵抗中的作用

在国家自然科学基金和863计划资助下，我们进行长期的鼻咽癌辐射敏感性的研究。项目组前期通过转录组测序发现：BRCC3和RPA3在辐射抵抗复发组的表达明显高于辐射敏感无复发组；进一步研究发现，在鼻咽癌放射抵抗中，BRCC3和RPA3分别与BRCA1/2和RAD51密切相关。据此我们提出“BRCC3和RPA3分别通过BRCA1/2介导的非同源重组和RPA3-RAD51介导的同源重组来修复DNA双链断裂、促进鼻咽癌辐射抵抗”的科学假设。为验证这一假设，本项目拟在大宗病例的鼻咽癌组织中检测并明确BRCC3和RPA3表达与放疗疗效的相关性；在细胞和动物模型中进行放射敏感性的功能验证；进一步通过启动子区域转录因子、甲基化等分析并结合体内外模型和临床标本检测、解析这两个基因导致鼻咽癌放射抵抗分子机制。项目的完成将为确证鼻咽癌辐射抗拒干预靶点、提高病人放疗疗效和减少放疗副作用提供实验研究的基础。

With the support of the National Natural Science Foundation of China and the 863 Program, we conducted long-term radiosensitivity studies on nasopharyngeal carcinoma. The transcriptome sequencing displayed that BRCC3 and RPA3 expression in radiation-resistant relapse group was significantly higher than the radiation-sensitive non-recurrence group. Through further studies, we found that BRCC3 and RPA3 were closely related to BRCA1/2 and RAD51 in nasopharyngeal carcinoma radioresistance respectively. Accordingly, we propose the scientific hypothesis that "BRCC3 and RPA3 repair DNA double-strand breaks through BRCA1/2-mediated non homologous end join repair and RPA3-RAD51-mediated homologous recombination repair, respectively. Then they promote radiation resistance of nasopharyngeal carcinoma". In order to verify the above scientific hypothesis, firstly, We have collected nasopharyngeal carcinoma tissue to detect the relationship between the expression of BRCC3 and RPA3 and radiotherapy effect. The next, We performed radiosensitivity functional validation on cell and animal models. Finally, Through the analysis of promoter region transcription factors, methylation and other in vitro/in vivo models, and clinical tissue samples, we elucidate the molecular mechanisms of BRCC3 and RPA3 that lead to the radiation resistance of nasopharyngeal carcinoma. The completion of the project will provide the basis for confirming the intervention target of radioresistance of nasopharyngeal carcinoma, improving the efficacy of radiotherapy for patients and reducing the side effects of radiotherapy.