鼻咽癌(Nasopharyngeal carcinoma, NPC)起源于鼻咽部假复层纤毛柱状上皮，后者由基底细胞和分化的管腔细胞（包括纤毛细胞和分泌细胞）组成。绝大多数NPC高表达基底细胞抗原，低表达管腔细胞抗原，表明NPC癌变过程中发生了基底细胞朝管腔细胞分化阻滞。本项目采用不同分化状态的NPC细胞建立了分化相关的超级增强子（super-enhancer, SE）谱和差异转录组，发现透明质酸合成酶HAS3在NPC组织中高表达，是基底型SE驱动的分化相关候选癌基因，提出SE驱动HAS3过度表达引起透明质酸（hyaluronan，HA）代谢异常是阻断鼻咽基底-管腔分化的原因。本项目拟鉴定调控HAS3-SE的转录相关蛋白质机器，深入研究SE驱动HAS3表达和HA代谢异常的转录与表观遗传机制，明确HA代谢异常在NPC分化中的作用和机理，建立基于基底-管腔生理分化方向的NPC分子分型模型。

Nasopharyngeal carcinoma(NPC) is a subtype of head and neck suqmous carcinoma and originate from malignant transformation of pseudostratified ciliated columnar epithelium which is consist of basal cells and differentiated luminal cells including ciliated cells and goblet secretory cells. The majority of NPC samples exhibit high level of basal cells antigens such as p63, KRT5, whereas low level of luminal cells antigens, suggesting differentiation from basal cells to luminal cells was blocked during NPC development. In this study, two NPC cell lines with distinct differentiation status were used to establish differentiation related super-enhancer(SE) landscape and differential transcriptome. Among the differential expressed genes, HAS3 is a candidate oncogene driven by basal type SE and overexpressed in NPC samples. We proposed that overexpression of HAS3 driven by basal type SE lead to hyaluronan(HA) metabolism alteration, which in turn block basal to luminal differentiation of NPE and contribute to NPC development. We plan to further investigate the transcriptional or epigenetic role of HAS3-SE in regulation of HAS3 expression and HA metabolism. One of the aim of this study is to identify the protein machine which is responsible for controlling HAS3-SE establishment and maintenance during NPC oncogenesis. Another aim is to study the role and underlying mechanisms of HA accumulation on NPC differentiation and malignant behaviors. We also plan to establish a novel molucular classification system based on basal-luminal differentiation markers for NPC diagnosis and prognosis.