长链非编码RNA HOTAIR在食管鳞状细胞恶性转化中的功能和调控机制研究

Long non-coding RNA (lncRNA) HOTAIR is involved in regulation of cell growth, differentiation, apoptosis and cell cycle control. However, its role in malignant transformation of esophageal squamous cells is still unclear. Our previous studies demonstrated that lncRNA HOTAIR expression was significantly up-regulated in esophageal squamous cell carcinoma tissues compared to normal tissues. After knocking-down lncRNA HOTAIR expression with its siRNA, we observed significantly depressed proliferation of esophageal cancer cells. In the preliminary study on how this lncRNA is regulated, we found that there is an intronic promoter in intron 2 of the HOTAIR gene. A genetic variation (rs920777 C→T) located in this promoter was significantly associated with increased risk of esophageal squamous cell carcinoma. Interestingly, this C→T change may influence binding of transcription factor Sp1 to DNA. That is, there might be Sp1 binding for individuals who carrying C allele, but no such binding for T allele carriers. In addition, there are three CpG islands in the HOTAIR gene locus, which may be potentially modified by DNA methylation and involved in expression regulation of this lncRNA. Based on the aforementioned results, we aimed to reveal the exact genetic and epigenetic mechanisms on how lncRNA HOTAIR is differentially regulated in malignant esophageal squamous cells and normal cells. Also, the biological role of lncRNA HOTAIR during malignant transformation of esophageal squamous cells will be investigated. The results of this study will initially explain how lncRNA is involved in development of esophageal squamous cell carcinoma, which may not only extend our understanding on the etiology of this lethal disease, but also provide theoretical supports for lncRNA-based drug development and discovery of diagnostic markers.

长链非编码RNA HOTAIR参与了细胞生长、分化、凋亡和细胞周期等各层面的调控，但其在食管鳞状细胞恶性转化中的作用仍不清楚。我们的前期研究发现，HOTAIR在食管鳞癌组织中的表达显著上调；利用siRNA对其基因沉默后，食管癌细胞恶性增殖受到显著抑制。在对其表达调控机制的初步研究中，我们发现：HOTAIR基因内含子2中存在一个启动子；位于上述启动子中的遗传变异rs920777 C→T与食管鳞癌发病风险显著相关，并可能影响转录因子Sp1的结合；同时，HOTAIR基因座位中存在3个潜在受DNA甲基化修饰调控的CpG岛。基于此，本项目拟深入研究导致HOTAIR在食管鳞癌中异常表达的遗传和表遗传调控机制，揭示HOTAIR在食管鳞状细胞恶变中的生物学功能。研究结果将初步阐释长链非编码RNA在食管鳞癌发生发展中的重要作用，拓宽对食管癌发病机制的理解，并为治疗药物的研发和诊断标志物的发现提供理论支撑。

长链非编码RNA （long non-coding RNA，lncRNA）HOTAIR参与了细胞生长、分化、凋亡和细胞周期等各层面的调控，但其在食管鳞状细胞恶性转化中的作用仍不清楚。我们的前期研究发现，HOTAIR在食管鳞癌组织中的表达显著上调；利用siRNA对其基因沉默后，食管癌细胞恶性增殖受到显著抑制。在对其表达调控机制的研究中，我们发现：HOTAIR基因内含子2中存在一个启动子；位于上述启动子中的遗传变异rs920778C→T与食管鳞癌发病风险显著相关；同时，HOTAIR基因座位中存在3个潜在受DNA甲基化修饰调控的CpG岛。本项目深入研究了导致HOTAIR在食管鳞癌中异常表达的遗传和表遗传调控机制，进而揭示了HOTAIR在食管鳞状细胞恶变中的生物学功能。研究结果初步阐释了lncRNA HOTAIR在食管鳞癌发生发展中的重要作用，拓宽对食管癌发病机制的理解，并为治疗药物的研发和诊断标志物的发现提供理论支撑。