EBV激活端粒酶是EBV致鼻咽癌早期关键步骤，PinX1是抑制端粒酶活性的抑癌基因，目前EBV通过PinX1调控端粒酶机制未明。我们已证实：EBV感染促进PinX1甲基化程度，PinX1异常高甲基化致其表达下调，DNMT3b是NF-κB调控的新靶基因，过表达LMP1可激活NF-κB上调DNMT3b以甲基化调控抑制PinX1表达；进一步预测PinX1启动子区也存在NF-κB结合位点。基于此提出本项目科学假说：PinX1可能是NF-κB调控的新靶基因，LMP1/NF-κB/DNMT3b/PinX1和LMP1/NF-κB/PinX1可能是活化端粒酶促进细胞增殖的两条新通路。拟构建EBV感染细胞动态转化模型，明确两通路在EBV致鼻咽癌不同阶段激活端粒酶对细胞功能的影响；以通路中关键分子为靶点诱导EBV进入裂解期并清除EBV感染细胞，为EBV感染致癌高危人群和鼻咽癌患者实施预测和有效治疗探索新思路。

Aberrant enhancement of telomerase activity by Epstein-Barr virus infection is believed to be a critical step in the early stage of carcinogenesis in nasopharyngeal carcinoma. Human PinX1, a potent tumor suppressor gene, has been elucidated as a novel telomerase inhibitor. However, the mechanism how EBV controls the activity of telomerase through PinX1 gene remains unclear. Our preliminary result showed that down-regulation of PinX1 expression in nasopharyngeal carcinoma was associated with aberrant CpG island hypermethylation of PinX1 gene. Furthermore, EBV infection could facilitate the degree of CpG island hypermethylation of PinX1. Moreover, DNMT3b has been identified as a novel target gene of NF-κB by our previously functional research. Finally, we clarify that LMP1, the oncoprotein of EBV, could upregulate DNMT3b expression and subsequently inhibit PinX1 expression through activation of NF-κB. On the other hand, two NF-κB binding sites in the 5’ flaking region of PinX1 gene have been predicted by bioinformatics analyses. On the basis of our preliminary results, we will demonstrate that PinX1 will be a novel target gene of NF-κB. Moreover, “LMP1/NF-κB/DNMT3b/PinX1” and “LMP1/NF-κB/PinX1”, which are two novel signaling pathways, could promote telomerase activity. Our further study will confirm that the role of these two novel signaling pathways in EBV LMP1-mediated enhancement of telomerase activity will be clarified in the process from oncogenic transformation of nasopharyngeal epithelia to the formation and development of nasopharyngeal carcinoma. Our research will provide new targets for prediction and therapy in Nasopharyngeal carcinoma, especially in nasopharyngeal carcinoma high-risk population who have been persistently infected with EBV, which will provide the profound scientific implication and superb value for clinical application.