TNKS1BP1偶联DNA-PKcs维持端粒稳定性调控食管鳞癌细胞放射抗拒性机制研究

Radioresistance is a major cause of failure in radiotherapy for esophageal squamous cell carcinoma (ESCC) patients, yet the potential mechanism has not been fully elucidated. A telomere is a region of repetitive nucleotide-protein complex at each end of a chromatid. A series of studies have shown that telomeres are targets for cancer cells radiosensitization. However, the role of DNA damge repair coupling of telomere maintenance still remains unclear. Here, our preliminary data revealed a significant negative correlation between overexpression of telomere protein TNKS1BP1 and overall survival of ESCC patients with post-operative radiotherapy. Knock-down of TNKS1BP1 substantially slowed down DNA repair for irradiation-induced DNA damage and increased the radiosensitivity of ESCC cells in vitro. In this project, we will further confirm the following hypothesis: TNKS1BP1 overexpression in ESCC may be involved in telomere DNA repair and maintenance, inhibition of mitotic catastrophe and promotion of radioresistance through the activation of DNA-PKcs, the key molecule of DNA repair pathway. Intervention of telomere stability mediated by TNKS1BP1/DNA-Pkcs pathway is expected to be a new target in the radiosensitization of ESCC. This project is likely to provide a new strategy for ESCC radiosensitization from the perspective of telomere stability coupled DNA damage response.

食管鳞癌（ESCC）所具有的放射抗拒性是引起放疗失败的主要原因，但机制并不完全清楚。端粒是位于染色体末端的重复DNA-蛋白质复合体，大量研究表明端粒是肿瘤放射增敏的靶点，但端粒与电离辐射引起的DNA损伤修复偶联机制不明。我们前期结果发现端粒蛋白TNKS1BP1在ESCC中表达水平与术后放疗患者预后呈负相关；体外实验证实抑制TNKS1BP1表达延迟DNA双链断裂损伤修复，增加ESCC细胞辐射敏感性。本课题拟在前期研究基础上阐明以下科学假设：ESCC中高表达的端粒蛋白TNKS1BP1通过活化DNA损伤修复关键分子DNA-PKcs，参与端粒的损伤修复，维持端粒稳定性，减少有丝分裂灾变，增加ESCC的放射抗拒性；干预TNKS1BP1/DNA-PKcs通路介导的端粒稳定性可作为ESCC放疗增敏的新靶点。本项目有望从端粒稳定性偶联DNA损伤反应的角度为ESCC放射增敏提供新的策略和思路。

食管鳞状细胞癌（Esophageal squamous cell carcinoma, ESCC）是我国主要的食管癌类型，恶性程度高，预后差，易出现远端转移和复发。放射治疗是食管癌的主要治疗手段之一，但治疗效果不佳，生存率低。食管癌细胞所具有的放射抗拒性是诱发放疗失败的主要原因。项目组研究发现，具有放射抗性的食管鳞癌组织中TNKSBP1表达显著升高。下调TNKSBP1使癌细胞对电离辐射敏感性；TNKSBP1通过与FHL2相互作用激活CHK2/CDC25C/CDC2信号通路诱导G2-M阻滞，从而增强ESCC细胞的抗辐射能力；另一方面，TNKSBP1的高表达与食管鳞癌的不良预后相关，TNKSBP1能够增强ESCC细胞的致瘤能力和肿瘤细胞干性，提高食管癌侵袭转移能力，并且我们发现TNKSBP1参与调控Tankyrase/Axin1/β-catenin通路，进而影响食管癌干性和恶性程度。因此，TNKSBP1可能成为食管鳞癌治疗的理想生物标志物和治疗靶点。