基底型超级增强子驱动的透明质酸代谢异常在鼻咽癌分化障碍中的作用机制

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.

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。

鼻咽癌是我国南方和东南亚地区最常见的头颈部恶性肿瘤，起病隐匿，容易早期转移。正常鼻咽假复层纤毛柱状上皮由基底细胞、纤毛细胞和少量分泌细胞组成。基底细胞是上皮的祖细胞，在正常情况下朝纤毛细胞和分泌细胞分化。该项目言研究发现鼻咽癌变过程中存在明显的基底-腔面分化阻滞，表现为绝大多数鼻咽癌病例组织均高度表达基底细胞特异性蛋白，而腔面细胞蛋白普遍降低。确立了基底型、腔面型鼻咽癌细胞模型，并建立了基底-腔面分化相关的超级增强子图谱，发现基底型基因受超级增强子驱动，是这些基因在鼻咽癌组织中过度表达的重要原因。确立了ΔNp63α是富集于基底型超级增强子的关键转录因子，调控鼻咽癌基因网络。证明超级增强子导致EGFR在鼻咽癌中过度表达，促进鼻咽癌远处转移。证实了HAS3受超级增强子调控，在基底型鼻咽癌细胞中高表达。抑制HAS3表达或活性，导致鼻咽癌细胞增殖、侵袭转移能力显著降低。项目执行期间课题组共发表SCI论文16篇，代表性成果发表在Carcinogenesis、J Exp Clin Cancer Res、Cancer Letters、Molecular Oncology等知名期刊。项目执行期间获批国家发明专利3项。获得湖南省医学科技奖一等奖1项。