环状RNA circVIL1在胃癌发生发展中的作用及分子机制研究

Gastric cancer (GC) is one of the most common digestive system tumors. Even with the opportunity to receive comprehensive treatment, the overall prognosis of gastric cancer is poor. Recently, scientists found that circular RNA (circRNA) molecules, rather than linear RNA molecules, are a common phenomenon in gene expression in human cells. It plays an important role in the development of many kinds of tumors. Previously we analyzed the expression profiles of circRNAs in advanced gastric adenocarcinoma tissues and adjacent normal mucosa tissues by biochips. We found that the expression of circVIL1 is significantly upregulated in GC tissues compared to adjacent normal mucosa tissues. In vitro assays showed that silencing of circVIL1 significantly suppressed GC cell proliferation, migration and invasion. Furtermore, bioinformatics and dual-luciferase analysis found that circVIL1 can combine competitively with miR-615-5p. On this basis, we will further investigate the functions of circVIL1, the possible mechaniam of miR-615-5p regulation by circVIL1 and the downstream target genes of miR-615-5p in GC. At the same time, we will detect the expression of circVIL1 in a large number of GC samples, analyze the relationship with clinical pathological characteristics and prognosis of patients. Our study will provide a new perspective on gastric cancer metastasis and recurrence and the findings of this study may contribute to the treatment and diagnosis of gastric cancer.

胃癌是最常见的消化系统肿瘤之一。最近，科学家们发现环状RNA比线性RNA更加稳定，并大量存在于真核细胞转录组中，具有临床诊断及预后标志物的潜在应用价值。我们前期对胃癌组织和癌旁正常组织进行了circRNA芯片检测，发现circVIL1在胃癌组织中表达显著上调。体外功能研究发现circVIL1 siRNA能抑制胃癌细胞的恶性增殖、侵袭和迁移能力。已知circRNA能够竞争性结合miRNA，抑制其对应mRNA的降解作用。前期研究发现circVIL1有miR-615-5p结合位点，能调控miR-615-5p表达。本研究在此基础上，阐明circVIL1在胃癌发生发展中的作用及circVIL1对下游miR-615-5p、靶基因的调控机制。同时，我们将检测大样本胃癌组织中circVIL1的表达，分析与临床病理特征及预后关系。本项目有望拓展对circRNA的认识，为寻找胃癌转移新的治疗靶标提供理论依据。

近年来，长链非编码RNA SLCO4A1反义RNA 1 (SLCO4A1- as1)已被证明在多种癌症类型中发挥致癌基因的作用，但SLCO4A1- as1在胃癌(GC)中的作用及其潜在的分子机制尚不清楚。在本研究中，我们发现SLCO4A1-AS1在GC样本和细胞系中均显著上调，且高水平的SLCO4A1-AS1与肿瘤晚期和患者生存期缩短相关。从机制上讲，SLCO4A1-AS1转录后调控了X-linked inhibitor of apoptosis (XIAP)，通过在GC中作为一种竞争性内源性RNA来调控miR-149。进一步的功能检测显示，过表达miR-149和敲低XIAP在体外显著抑制了GC细胞的活力、迁移和侵袭特性。SLCO4A1-AS1表达的下调也确定了GC细胞的功能，但在体外被miR-149抑制物削弱。最后，我们证明了SLCO4A1-AS1的缺失在体内抑制了肿瘤的生长和转移。总之，这些发现表明SLCO4A1-AS1在GC中起着重要的致癌lncRNA的作用。通过与miR-149相互作用，增强XIAP的表达，促进胃癌的生长和转移。因此，SLCO4A1-AS1是一种潜在的胃癌治疗新靶点。