新发现的环状RNAcirc_0003692编码多肽FNDC3B-276aa竞争结合TRIP13蛋白抑制胃癌生长和转移的作用机制研究

胃癌的发病率和死亡率在我国位居前列，易转移是其预后差的重要原因之一。环状RNA密切参与肿瘤的发生与进展，但在胃癌转移中的作用尚未完全阐明。课题组前期新鉴定出circ_0003692在胃癌中表达显著下调，能抑制胃癌生长和转移。更重要的是，我们发现circ_0003692具有翻译能力。基于前期实验和文献，我们提出假说：circ_0003692可翻译蛋白FNDC3B-276aa，作为FNDC3B异构体，与其竞争结合TRIP13，调控靶基因MYC，抑制胃癌生长和转移。同时，胃癌中高表达的RNA编辑蛋白ADAR1，通过作用于Alu元件，抑制circ_0003692的表达。本项目拟利用慢病毒、环状RNA翻译鉴定、RNA-蛋白、蛋白-蛋白、环状RNA形成鉴定等实验，证实FNDC3B-276aa的抑癌作用，鉴定其下游结合蛋白和上游表达调控机制，以验证我们的假说。这将为进一步阐明胃癌的转移机制提供新思路。

Gastric cancer (GC) is one of the most common malignant tumors in China, and metastasis is an important reason for poor prognosis of GC. circRNAs are novel non-coding RNAs with important regulatory role, growing evidence has shown that circRNAs are involved in the occurrence and progression of cancer, but its role in the metastasis of GC has not been fully elucidated. Our previous study identified a novel circRNA named as circ_0003692. We found circ_0003692 was significantly down-regulated in gastric cancer tissues, and circ_0003692 was able to suppress the proliferation and metastasis of gastric cancer cells in vitro. More importantly, we found that circ_0003692 had the ability of translation. Based on previous experiments and literatures, we hypothesized that circ_0003692 can translate the protein FNDC3B-276aa, as the isoform of FNDC3B protein. FNDC3B-276aa can competitively bind TRIP13, regulate the target gene MYC and inhibit the growth and metastasis of gastric cancer. Meanwhile, ADAR1, a highly expressed RNA editing protein in gastric cancer, can inhibit the expression of circ_0003692 by binding to Alu elements of circRNA. In current project, we plan to confirm the antitumor effect of FNDC3B-276aa, identify its downstream binding protein and upstream expression regulation mechanism, and verify our hypothesis by using circRNA lentivirus, circRNA translation identification technology, RNA-protein interaction platform, protein-protein interaction platform, circRNA formation identification assays and other experiments. This will provide new clues to elucidate the mechanism of metastasis of gastric cancer.