新型亚细胞核结构Paraspeckle的形成及其促进胃癌进展的机制和临床应用研究

胃癌是人类常见恶性肿瘤之一,五年生存率不足25%；新型亚细胞核结构Paraspeckle在其中的作用和机制不清。我们前期研究首次发现WTX缺失与胃癌进展相关、WTX调控Paraspeckle关键骨架分子LncRNA NEAT1表达、miR-17家族介导WTX缺失；结合文献报道Paraspeckle分子与WTX存在共定位，推测miR-17家族沉默WTX，通过NEAT1影响Paraspeckle形成而调控胃癌进展。为验证这一假说并揭示其在胃癌发生发展中的功能机制及临床价值，本研究将分析胃癌中Paraspeckle形成情况、miR-17家族和WTX对NEAT1表达和Paraspeckle形成影响、功能和相互作用以及对化疗药物的反应；结合裸鼠及基因敲除小鼠胃原位癌模型整体验证以及新靶点筛选，研究将揭示胃癌进展过程中Paraspeckle形成机制、功能意义和临床价值，为胃癌机制和治疗研究提供新方向。

Gastric cancer is one of the common human malignancies. Its 5-years survival rate is less than 25%.Paraspeckle is the new subnuclear structure whose function and mechanism are unclear. Our study firstly found that WTX loss correlated with gastric cancer progress, WTX targeted, the Paraspeckle skeleton molecule, LncRNA NEAT1, and miR-17 family induced WTX loss. Combining with the previous report that there are co-location of Paraspeckle and WTX, we suppose that miR-17 family silences WTX, then influences the formation of Paraspeckle through binding NEAT1 and regulating the progress of gastric cancer. To test this hypothesis, uncover the function, mechanism and clinical value of Paraspeckle in gastric cancer, this study will analyze the formation of Paraspeckle in gastric cancer, the function and mechanism of miR-17/WTX to NEAT1 expression and Paraspeckle formation by using qRT-PCR, immunofluorescence and Structured Illumination Microscopy (SIM); explore functional regulation by the cell function and protein expression and interaction experiment; and analysis the response and mechanism of Paraspeckle formation to chemotherapy. The gastric carcinoma in situ mice model will be established in WTX gene knockout mice or nude mice to validate the mechanism and clinical values in vivo. The new targets of Paraspeckle will be screened by ChIP analysis. Overall, this study will reveal the mechanism, function and clinical value of Paraspeckle formation during the tumorigenesis, provide a new direction for the mechanism studying and treatment of gastric cancer.