TIMELESS诱导鼻咽癌放疗抵抗的分子机制

At present, radiotherapy is the main treatment for nasopharyngeal carcinoma (NPC) . Radio-resistance is the main reason leading to greatly reduced cure rate of NPC. Studies found that NF-κB is a key factor in the radio-resistance of tumor cells. Recently, our study found that TBLR1 activates NF-kB signaling pathway to inhibit the apoptosis and reduce the sensitivity of nasopharyngeal carcinoma cells to radiotherapy and chemotherapy (Correspondent Molecular cancer IF = 5.397). In the study of the mechanism of NF-κB signaling pathway affecting the radio-sensitivity of nasopharyngeal carcinoma, we found that TIMELESS can activate NF-κB signaling pathway to affect the radio-sensitivity of nasopharyngeal carcinoma, but its detailed molecular mechanism needs to be clarified. In this project, the molecular mechanism of TIMELESS activation of NF-κB signaling pathway and the promotion of anti-apoptosis to induce the radio-resistance of nasopharyngeal carcinoma cells were studied by cell, molecular biology and animal experiments. The relationship of TIMELESS and NF-κB pathway will be confirmed from clinical specimens to further explore the molecular mechanism of TIMELESS to promote the radio-resistance of nasopharyngeal carcinoma. This will provide a new theoretical basis for early prediction of radio-resistance and providing a new target for treatment of nasopharyngeal carcinoma.

目前放射治疗是鼻咽癌的首选治疗方式，放疗抵抗是导致鼻咽癌治愈率大大降低的最主要原因。相关研究发现NF-κB是导致肿瘤细胞辐射抵抗的关键因素。近期我们的研究发现TBLR1激活NF-kB信号通路抑制鼻咽癌细胞的凋亡，降低鼻咽癌细胞对放化疗的敏感性（通讯作者 Molecular cancer IF=5.397）。在深入研究NF-kB信号通路影响鼻咽癌放疗敏感性的机制时我们发现TIMELESS可激活NF-κB信号通路进而影响鼻咽癌放疗敏感性，然而其详细分子机制有待阐明。本项目采用细胞、分子生物学及动物实验探讨TIMELESS激活NF-κB信号通路，促进抗凋亡作用诱导鼻咽癌细胞发生放射抵抗的详细分子机制；并从临床标本中验证TIMELESS与NF-κB通路的关系，深层次解析TIMELESS促进鼻咽癌放疗抵抗的分子机制，为早期预测鼻咽癌放疗抵抗提供新的理论依据，为治疗提供新的靶点。

目前放射治疗是鼻咽癌的首选治疗方式，放疗抵抗是导致鼻咽癌治愈率大大降低的最主要原因。本研究旨在探讨TIMELESS促进鼻咽癌放疗抵抗的分子机制。本课题组发现TIMELESS基因在鼻咽癌细胞及组织中高表达，高表达TIMELESS与鼻咽癌不良预后显著相关。进一步分子机制研究结果表明，高表达TIMELESS可激活NF-κB信号通路并可增强鼻咽癌干细胞特性及促进放射治疗后的 DNA 损伤修复导致放射治疗抵抗。本研究成果表明：TIMELESS促进鼻咽癌放疗抵抗中发挥重要作用，为早期预测鼻咽癌放疗抵抗提供新的理论依据，为治疗提供新的靶点。