Y染色体连锁LINC00278调控ZFY基因可变剪接促进男性食管鳞癌发生发展的分子机制研究

There is a significant gender bias in the incidence of esophageal squamous cell carcinoma, and the genetic factors that cause this difference are not yet clear. In the pre-trials, we analyzed the RNA-Seq data of different sex esophageal squamous cell carcinoma samples. It was found that Y chromosome-linked LINC00278 was differentially expressed in male esophageal squamous cell carcinoma samples. Further studies showed that the lncRNA might be involved in the ZFY gene alternative splicing, resulting in the formation of truncated ZFY-2 variants that could associate with BORIS/CTCFL to function in downstream pathways. Accordingly, we hypothesized that this lncRNA could influence the development of male esophageal squamous cell carcinoma through regulating ZFY gene alternative splicing characteristically. On the basis of these results, we intend to use the method of double center large sample analysis, mechanism research and functional phenotypic experiments to clarify the role of lncRNA in male esophageal squamous cell carcinoma. In order to reveal the possible genetic factors that cause sex differences in esophageal squamous cell carcinoma and provide scientific basis and means for the prevention and treatment of esophageal squamous cell carcinoma.

食管鳞癌的发病存在着显著的性别差异，造成这种差异的遗传因素尚不明确。前期预实验中我们通过对不同性别食管鳞癌样本的RNA-Seq数据进行分析发现Y染色体连锁的LINC00278在男性食管鳞癌样本中存在着差异表达；进一步研究显示该LncRNA可能参与了ZFY基因的可变剪接，促成了截短型的ZFY-2变体的形成，该剪接体可以与BORIS/CTCFL结合以此作用于下游通路。据此，我们假设该LncRNA可以通过调控ZFY基因可变剪接的方式“特征性”的影响男性食管鳞癌的发生发展。本项目拟在此基础上，联合使用双中心大样本分析、机制研究和功能表型实验等方法系统的阐明该LncRNA的异常表达在男性食管鳞癌中的作用。以期揭示造成食管鳞癌发病性别差异的可能遗传因素，并为食管鳞癌的防治提供科学依据和手段。

食管鳞癌的发病存在着显著的性别差异，前期研究中我们通过对不同性别食管鳞癌样本的RNA-Seq数据进行分析发现Y染色体连锁的LINC00278在男性食管鳞癌样本中存在着差异表达；进一步研究显示该LncRNA能够编码一个结合于YY1蛋白上的微肽YY1BM，其作用为抑制YY1与AR的结合，从而抑制它们共同调控的基因eEF2K的转录。在食管鳞状细胞癌组织和细胞中低表达的YY1BM导致了eEF2K的高表达，抑制了癌细胞在营养缺乏条件下的凋亡。此外，吸烟通过减少LINC00278的m6A修饰降低YY1BM的翻译；同时，人工合成的YY1BM对男性食管鳞癌具有抑制作用。我们的研究揭示造成食管鳞癌发病性别差异的能遗传因素，并为食管鳞癌的防治提供科学依据和手段。