Alu RNA调控NFκB信号通路促进胃癌发生与发展的分子机制研究

Gastric cancer (GC) is a kind of malignant tumor with high morbidity and mortality rates worldwide. It is reported non-coding RNAs serve the important role in regulating pro-inflammatory signaling in gastric cancer. Alu RNA, a family of transcripts of Alu element that accounts for 10% of human genome, was rarely addressed to its biological function in gastric carcinogenesis and progression as a family of non-coding RNA. Our group previously found Alu RNA accumulated in GC tissues and probably facilitated the activation of NFκB and STAT3 pathway, suggesting its participation in GC pro-inflammatory network. Here we plan to uncover direct/indirect molecules that interact with Alu RNA and to elucidate the mechanism of how Alu RNA, especially its subfamilies mainly expressed in gastric cancer, regulates the pro-inflammatory NFκB and downstream STAT3 pathway by molecular biological methods such as gene transfection, immunoblot, RNA immunoprecipitation, real-time PCR, etc. This study would finally lay the theoretical foundation of gastric cancer pathogenesis from the perspectives of non-coding Alu RNA regulation, and might put forward a novel target or strategy for GC diagnosis and therapy.

胃癌是中国乃至世界发病率和死亡率较高的恶性肿瘤，研究发现非编码RNA在胃癌发生发展相关促炎信号通路中起重要作用。Alu RNA是一个由占人类基因组约10%的Alu元件转录产生的非编码RNA家族，然而目前尚无关于Alu RNA在胃癌发生发展中生物学功能的报道。我们前期研究显示，Alu RNA在早期胃癌组织中大量表达并促进了炎性通路NFκB、STAT3活化，提示Alu RNA很可能参与胃癌炎症信号通路的调控。本课题拟通过研究Alu RNA及其主要亚型与胃癌发生发展的相关性，采用体外基因转染、免疫印迹、RNA免疫沉淀、实时定量PCR等细胞和分子生物学方法，揭示Alu RNA下游直接/间接的信号转导分子，阐明Alu RNA及其主要亚型调控NFκB及下游STAT3促炎通路的分子机制，为从Alu RNA调控的角度阐述胃癌发生发展的分子机制提供实验依据和理论基础，为胃癌早期诊断和治疗提供候选分子和策略。

胃癌是中国乃至世界发病率和死亡率较高的恶性肿瘤，研究发现非编码RNA在胃癌发生发展相关促炎信号通路中起重要作用。Alu RNA是一个由占人类基因组约10%的Alu元件转录产生的非编码RNA家族，然而目前关于Alu RNA生物学功能的研究较为匮乏，且尚无Alu RNA在胃癌发生发展中生物学功能的报道。本研究通过分子生物学、免疫学、组学等方法建立了实验室基于qPCR定量检测Alu RNA的方法，揭示了Alu RNA与胃癌发生发展的密切相关性，发现在中国西北人群中主要表达Alu Sb亚型；尽管许多研究认为STAT3与NFκB具有协同相关的活化特点，本研究发现过表达Alu RNA主要激活STAT3活化，对NFκB活化的影响不显著，而且我们进一步阐明了Alu RNA通过ceRNA的方式负调控miR-3159从而促进IRF1表达，起到了在胃癌细胞中维持IRF1和STAT3表达活化的功能。本研究揭示了Alu RNA新的生物学功能，为进一步理解胃癌的发生发展提供了新视角，深入研究可能将有望发现新的抗癌靶点。