linc00312及其遗传变异在鼻咽癌治疗中的作用及机制研究

Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China, especially in Hunan and Guangdong provinces, with its morbidity ranking the first in the world. Though several Genome-wide association studies (GWAS) have identified a number of genetic biomarkers for NPC susceptibility, the role of genetic variations in the efficacy and prognosis of NPC treatment is still unclear. To date, the effect of long non-coding RNA (lncRNA) genetic variations on NPC prognosis has never been reported. Our previous study demonstrated that linc00312 rs12497104 was significantly associated with increased risk of NPC and poor short-term efficacy. Over-expression of linc00312 could increase the sensitivity of NPC cells to cisplatin and radiation induced toxic reactions. Therefore, we intend to confirm the correlation between linc00312 genetic variations and NPC prognosis in multicenter samples and apply target sequencing to excavate novel genetic variations of linc00312. Then, we would make clear the role of linc00312 and its genetic variations in NPC chemoradiosensitivity. Moreover, by applying RNA-seq technique, we would identify the downstream signal pathways of linc00312 that involved in NPC prognosis regulation. This project will help us discover new predictive molecular markers for NPC, and explore new strategies to improve the poor prognosis of NPC, which is of great significance for individualized treatment of NPC.

鼻咽癌在我国南方如湖南、广东等地发病率高居世界首位。多项GWAS研究证实遗传因素与鼻咽癌发病风险相关，但基因变异在鼻咽癌治疗和预后中的作用尚未完全揭示，尤其是lncRNA遗传变异对鼻咽癌预后的影响至今未见报道。我们前期研究首次证实linc00312 rs12497104突变显著增加鼻咽癌发生风险并与较差预后有关，高表达linc00312明显增加NPC细胞对顺铂和放射线的敏感性。本项目旨在:1.完成linc00312遗传变异作为鼻咽癌预后分子靶标的人群验证并应用靶向测序发掘有预测价值的新变异位点；2.阐明linc00312及其基因变异在鼻咽癌治疗敏感性中的作用；3.应用RNA-seq等技术查明决定鼻咽癌预后的linc00312下游关键基因及信号通路。本项目的完成有助于发掘新的有预测价值的鼻咽癌分子分型靶标，探索鼻咽癌预后不良的新对策及早期干预措施，对鼻咽癌的个体化治疗具有重要意义。

鼻咽癌在我国南方如湖南、广东等地发病率高居世界首位。多项GWAS研究证实遗传因素与鼻咽癌发病风险相关，但基因变异在鼻咽癌治疗和预后中的作用尚未完全揭示，尤其是lncRNA遗传变异对鼻咽癌预后的影响至今未见报道。我们前期研究首次证实linc00312 rs12497104突变显著增加鼻咽癌发生风险并与较差预后有关，高表达linc00312明显增加鼻咽癌细胞对顺铂和放射线的敏感性。近期，我们完成684例鼻咽癌患者的随访，针对lncRNA遗传变异的研究新发现.Linc00312、LINC-PINT的遗传变异与鼻咽癌患者同步放化疗期间毒性反应和无远处转移生存相关。通过放射干预处理，采用放射敏感性克隆存活实验、流式细胞术、裸鼠成瘤等生物学实验技术，确证Linc00312、LINC-PINT可增加鼻咽癌细胞对放射线的敏感性。通过RNA pull down、免疫荧光检测和Agilent RNA表达谱芯片分析lncRNA放疗增敏作用的靶蛋白和下游信号通路。探索上述lncRNA对鼻咽癌细胞放射敏感性的影响并解释其潜在分子机制，为鼻咽癌个体化放射治疗提供分子靶标。