转录因子Hes1靶向EZH2调控鼻咽癌分化的研究

绝大多数鼻咽癌属于未分化癌，为研究实体肿瘤的诱导分化治疗提供了一个独特的模型。我们前期研究发现，Hes1在鼻咽癌分化过程中可能起抗分化的作用，EZH2是Hes1的靶基因，Hes1正向调控EZH2的表达，而新近研究证实沉默EZH2表达可促进鼻咽癌细胞分化，这些提示Hes1有可能通过EZH2调控鼻咽癌细胞的分化。基此，本项目拟进一步系统阐明Hes1在鼻咽癌分化过程中的作用，并确证Hes1调控鼻咽癌细胞分化的作用可否由EZH2介导。其次收集表达shHes1和对照的鼻咽癌细胞，采用RNA测序筛选差异表达基因，并利用生物信息学软件预测Hes1影响鼻咽癌细胞分化的可能机制与调控网络，进而功能验证。最后探讨siRNA-Hes1单药或联合放疗的体内抑瘤效果；临床标本验证Hes1和EZH2与分化基因、干性基因和辐射抗性基因等表达相关性及临床病理意义。预期成果将为鼻咽癌诱导分化治疗提供理论依据及潜在治疗靶标。

More than 95% of nasopharyngeal carcinoma (NPCs) are pathologically diagnosed as Type III undifferentiated carcinomas, which provides a unique model for investigating the differentiation therapy of solid tumors. Our preliminary studies reveal that (1) Hes1 may play a role of anti-differentiation in NPC, (2) EZH2 is a target gene of Hes1 and Hes1 positively regulates the EZH2 expression. Recent study showed that silencing EZH2 expression by RNA interference promotes the differentiation of NPC cells. These aforementioned findings suggest that Hes1 regulates NPC cell differentiation by its target gene EZH2. Based on this, the project will further define the roles of Hes1 in NPC differentiation, and then confirm that the function of Hes1 in NPC differentiation can be mediated by its target gene EZH2. Secondly, the cells expressing shHes1 or shSCR are collected, followed by RNA sequencing to screen the differentially expressed genes, and predicting the mechanism involving in Hes1-mediated NPC differentiation. Finally, this project plans to explore the in vivo inhibitory effects of siRNA-Hes1 alone or in combination with radiotherapy on NPC cells, and the clinical specimens verifies the relationship between Hes1 & EZH2 and differentiation-related genes, stemness genes and radiation resistance genes. Finally, the expected results will provide theoretical basis and potential therapeutic targets for the differentiation therapy of NPC.