食管鳞癌特异性TP63超级增强子元件的功能及形成机制研究

超级增强子是由多个相邻增强子组成的一个大簇顺式调控元件，在多种癌症类型中介导了癌症的转录失调。食管鳞状细胞癌（以下简称“食管鳞癌”）是中国地区高发的最具侵袭性恶性肿瘤之一，目前仍缺乏有效的靶向治疗药物。文献和我们的研究表明TP63是食管鳞癌的核心转录因子，通过超级增强子调控下游多个癌基因的表达而维持食管鳞癌的多种恶性表型；同时TP63的表达也受自身超级增强子的调控。然而，食管鳞癌特异性的TP63超级增强子功能元件是什么及其形成机制均不清楚。本项目拟在我们前期研究和预实验的基础上，进一步明确食管鳞癌特异性的TP63超级增强子功能元件，阐明其形成机制，并揭示TP63超级增强子功能元件eRNA表达的临床意义。本项目的研究将为破译食管鳞癌中TP63的精确调控奠定强有力的理论基础，为食管鳞癌的临床诊治提供新型候选分子标志物和潜在药物靶点。

Super-enhancers (SEs) are large clusters of genomic regulatory elements. SEs promote transcription dysregulation across various kinds of human cancers in a cancer-type-specific manner. Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy. Researchers’ and our previous work have established the fundamental role of TP63 in promoting ESCC development by regulating the expression of several oncogene through SEs in an ESCC-specific manner including TP63 itself. However, issues about which SE elements of TP63 exist only in ESCC cancer cells but not normal cells, whether they are functional SE elements in mediating transcription of TP63 and tumor progression, and mechanism of SE’s formation are still unappreciated. Based on our previous findings and preliminary data, this study will identify ESCC-specific functional enhancers of TP63; decipher the mechanism of those ESCC-specific SEs; and reveal clinical significance of the expression of TP63 functional enhancers (eRNA level). Our findings have far­reaching implications in understanding of the precise regulation of TP63 in ESCC and be of utmost significance to all those scientists working in the field of squamous malignancies. These advances will provide novel candidate molecular markers and potential targets for clinical diagnosis and treatment of ESCC.