鼻咽癌放疗过程中癌细胞容易发生放疗抵抗而降低疗效，出现恶化和复发，放疗抵抗核心机制仍然未知。生物大数据分析，发现miR-101/PRKDC轴活化可能在鼻咽癌放疗抵抗的核心机制。预实验发现，鼻咽癌放疗抵抗细胞中，提升miR-101表达，可显著增加细胞对射线的敏感性。因此，若能将miR-101高效转入鼻咽癌细胞，并控制性启动它表达，可望调控miR-101/PRKDC轴而逆转细胞放疗抵抗。本项目拟构建一种羧甲基壳聚糖纳米微粒，其内包裹E9（放射敏感增强子）和hTERTp（人端粒酶启动子）串连组成的“基因开关”调控miR-101表达的质粒载体。此纳米微粒不仅水溶性好、易被癌细胞摄取，还可使miR-101特异性表达于鼻咽癌细胞中，并在放射作用下增强表达；上调的miR-101可通过靶向沉默PRKDC、继而调控下游生存信号通路而实现放疗增敏。本课题对探索放疗抵抗机制和探寻鼻咽癌治疗靶点具有重要意义。

Radiotherapy is an important method for the treatment of nasopharyngeal carcinoma (NPC), but the efficacy was reduced owing to the occurrence of radio-resistance, leading to deterioration and recurrence of cancer. A variety of mechanisms are involved in NPC radioresistance, but the core genes and pathways are still unknown. In this study, bioinformatics analysis of gene microarray data, combined with pre-experimental validation, showed that miR-101/PRKDC axis activation may play a central role in radioresistance of nasopharyngeal carcinoma. Preliminary experiments showed that the increased expression of miR-101 in NPC radioresistant cells could significantly increase the sensitivity of cells to radiation. Thus, we hypothesized that transfection with miR-101 into the cancer cells might reverse the radioresistance via inhibition of miR-101/PRKDC axis. On the basis of the research results, we aim to construct a nano-carrier comprising miR-101 driven by e9 (the radiosensitivity enhancer) and hTERTp (cancer-specific promoter) that might specifically induce the expression of miR-101 in cancer cells. The vector is water-soluble and easily absorbed by cancer cells, which might effectively and specifically target the cancer cells and further reverse the radioresistance of the cells. The use of the composite nano-carrier might help understand in great depth the mechanisms of radioresistance and facilitate looking for new therapeutic strategies.