Rap1在TRF2介导的胃癌多药耐药中的作用及机制研究

Up to now, there have been numerous papers indicate the role of telomere in cancer multidrug-resistance (MDR). But most studies have been focused on telomerase activity and telomere length. For the first time, we found that telomeric protein TRF2 promotes gastric cancer MDR, but the mechanism remains unclear. Rap1 is the TRF2-interacting protein in the telomeric protein complex. Its stability and functions are closely associated with TRF2. Recent studies suggested that Rap1 is an adaptor protein with telomeric and extra-telomeric functions. With further study, we confirmed that Rap1 participated in TRF2-mediated gastric cancer MDR. Rap1 was critical for the functions of TRF2 in the anticancer-drugs induced DNA damage response. Rap1 was detectable both in nucleus and cytoplasm of gastric cancer cells. Rap1 expressions were regulated by TRF2. So we presume that Rap1 plays an important role in TRF2-mediated gastric cancer MDR through multiple mechanisms. The current study will investigate the role of Rap1 in TRF2-mediated gastric cancer MDR and the underlying mechanisms, such as DNA damage response induced by anticancer-drugs and NF-κB-mediated pathways. The study might be a fresh look into the role of telomere in cancer MDR and developing possible strategies to overcome cancer MDR.

端粒与肿瘤耐药相关，但多数研究集中于对端粒酶活性和端粒长度的检测。申请者首次发现端粒结合蛋白TRF2增加胃癌多药耐药性，是端粒参与肿瘤耐药的重要因子，但机制尚不完全明确。端粒结合蛋白Rap1是TRF2相互作用因子，其稳定性和功能与TRF2紧密相连。最新研究发现Rap1是具有多种端粒和端粒外功能的调控蛋白。我们进一步研究证实：Rap1参与TRF2介导的胃癌耐药、Rap1调控TRF2在化疗药物诱导的DNA损伤修复中的作用、胃癌细胞Rap1有胞浆表达、Rap1表达受TRF2调控。由此推测，Rap1通过多种机制参与TRF2介导的胃癌耐药。本研究将以前期工作为基础，明确Rap1在TRF2介导的胃癌耐药中的作用，并探讨TRF2/Rap1对化疗药物诱导的DNA损伤修复、NF-κB信号通路的影响，揭示Rap1在TRF2介导的胃癌多药耐药中的作用及机制，从新的视角阐明端粒参与肿瘤耐药发生的分子机制。

端粒结合蛋白TRF2增加胃癌多药耐药性，是端粒参与肿瘤耐药的重要因子，但机制尚不完全明确。端粒结合蛋白Rap1是TRF2相互作用因子，其稳定性和功能与TRF2紧密相连， 本研究证实（1）Rap1在胃癌细胞胞浆表达增高，通过调控NF-κB信号通路促进胃癌的发生发展; Rap1调控TRF2在化疗药物诱导的DNA损伤修复中的作用，与TRF2共同参与胃癌多药耐药的发生。.（2）TRF2在衰老小鼠大脑皮层表达明显降低；TRF2通过抑制DNA损伤修复参与神经元衰老，是端粒参与衰老及衰老相关疾病发生的重要因子。.（3）关于比较研究寿命显著不同的近缘啮齿类动物之间TRF2/Rap1蛋白表达水平的实验结果证实，TRF2/Rap1与衰老和癌症密切相关。