鼻咽癌是中国南方常见的头颈部恶性肿瘤，发病机制尚未完全阐明。细胞永生化是肿瘤发生的早期阶段，端粒酶激活是细胞永生化的关键步骤。文献报道，约85%的鼻咽癌检测出端粒酶活性。端粒酶主要由催化亚基TERT、RNA模板TERC组成。申请人首次发现TOE1通过调节TERC 3'末端加工从而调控端粒酶活性。已有证据显示，TOE1在头颈肿瘤中高表达并与生存率密切相关，其表达依赖于AKT/GSK3β信号通路。我们猜测，鼻咽癌细胞内部通过AKT/GSK3β通路促进TOE1表达，然后TOE1加工TERC 3'末端并靶向增强端粒酶活性，最终促进鼻咽癌的发生和发展。本项目拟1）探索TOE1调控端粒酶活性对鼻咽癌细胞生长、侵袭和迁移等生物学功能的影响；2）阐明鼻咽癌细胞调控TOE1表达的上游分子机制。本项目将从上而下揭示TOE1在鼻咽癌细胞中的调控网络，为鼻咽癌早期发病诊断提供新思路，为临床早期干预提供理论依据。

Nasopharyngeal carcinoma is a common head and neck malignancy in southern China, and its pathogenesis has not been fully elucidated. Cell immortalization is an early stage of tumorigenesis, and telomerase activation is a key step in cell immortalization. It is reported that about 85% of nasopharyngeal carcinomas has detected telomerase activity. Telomerase is mainly composed of catalytic subunit TERT and RNA template TERC. For the first time the applicant found that TOE1 regulates telomerase activity by modulating the 3’ end processing of TERC. Our preliminary data found that TOE1 is highly expressed in head and neck tumors, which depends on the AKT/GSK3β signaling pathway, and it is closely related to survival. We speculate that nasopharyngeal cancer cells internally promote TOE1 expression through the AKT/GSK3β pathway, and then TOE1 processes the 3’ end of TERC to enhance telomerase activity, ultimately promoting the occurrence and development of nasopharyngeal carcinoma. This project intends to 1) explore the effects of TOE1 regulation of telomerase activity on the biological functions of nasopharyngeal carcinoma cells such as growth, invasion and migration; 2) clarify the upstream molecular mechanism of nasopharyngeal carcinoma cells regulating TOE1 expression. This project will systematically reveal the regulatory network of TOE1 in nasopharyngeal cancer cells and provide new ideas for the early diagnosis of nasopharyngeal cancer, and provide a theoretical basis for early clinical intervention.