长链非编码RNA DGCR5在食管癌中选择性剪接的分子机制及其功能研究

近年研究表明，选择性剪接可介导长链非编码RNA（lncRNA）的异常生成，从而调控肿瘤的发生发展；然而，lncRNA在肿瘤中异常剪接的机制仍不清楚。近期我们研究发现：1、食管癌中选择性高表达lncRNA-DGCR5的促癌性短剪接体（DGCR5-S），并低表达抑癌性长剪接体（DGCR5-L）；2、Wnt/β-catenin信号的激活可促进FUS蛋白结合DGCR5前体，调节DGCR5的选择性剪接；3、进而，成熟的DGCR5通过吸附microRNAs反馈性维持Wnt/β-catenin信号活性，从而增强肿瘤细胞的自我更新能力和肿瘤起始能力。在此基础上，本项目将深入解析DGCR5异常剪接的机制和功能，并探讨反义寡核苷酸靶向DGCR5剪接而抑制肿瘤的作用。本研究不仅能够揭示lncRNA在食管癌中异常剪接的新机制，也将为食管癌的临床诊治提供新的分子标志物和靶点。

Recent studies have demonstrated that abnormal generation of long non-coding RNA (lncRNA) was mediated by RNA alternative splicing, thereby regulating the development of tumors. However, the mechanism of abnormal splicing of lncRNA in tumors remains unclear. Recently, we have found that: 1. Esophageal cancer selectively expresses lncRNA-DGCR5-tumor-promoting short spliceosome (DGCR5-S), but downregulates the tumor-suppressive long spliceosome (DGCR5-L). 2. The activation of Wnt/β-catenin signaling pathway promotes the binding of FUS protein to DGCR5 precursor and regulates the alternative splicing of DGCR5. 3. Further, mature DGCR5 maintains activity of Wnt/β-catenin signaling pathway through sponging microRNAs, thus enhancing the self-renewal and tumor-initiating ability of tumor cells. On this basis, we will deeply analyze the mechanism and function of DGCR5 abnormal splicing in esophageal cancer, and explore the role of antisense oligonucleotides in targeting DGCR5 splicing switch to suppress tumors. Our results will not only reveal a new mechanism of abnormal splicing of lncRNA, but also provide new molecular markers and targets for clinical diagnosis and treatment of esophageal cancer.