HNF1A-AS1激活CUL4A介导的PTEN泛素化降解促进胃癌转移的作用机制研究

长链非编码RNA(lncRNA)在肿瘤浸润和转移过程中发挥重要作用，HNF1A-AS1调控胃癌转移的机制尚未明了。前期我们发现HNF1A-AS1在转移组胃癌标本较非转移组表达明显增高，且在体外促进胃癌细胞迁移和浸润。我们验证了HNF1A-AS1的结合蛋白CUL4A和PTEN，推测它可能作为“脚手架”把CUL4A和PTEN连接在一起，促进CUL4A对PTEN的泛素化降解，从而激活后者下游的PI3K/AKT信号通路。本研究拟验证HNF1A-AS1在实验动物体内对胃癌转移的促进作用，明确其对CUL4A和PTEN的连接作用，及对下游信号通路的调控；确定HNF1A-AS1与其结合蛋白的关键结合位点，合成靶向HNF1A-AS1核心结合区的小分子锁核酸，验证其作为胃癌实验治疗靶点的潜在价值。该项目有望阐明HNF1A-AS1促进胃癌转移的分子机制，为胃癌治疗提供新的作用靶点，具有重要的临床意义和科学价值。

Long non-coding RNA (lncRNA) plays an important role in tumor invasion and metastasis. The mechanism of HNF1A-AS1 in regulating gastric cancer (GC) metastasis is not yet clear. Our data showed HNF1A-AS1 was significantly upregulated in the metastatic gastric cancer cases compared with the non-metastatic cases, and HNF1A-AS1 promote migration and invasion activity of GC cells. Further experiments showed that HNF1A-AS1，combined CUL4A and PTEN, may functions as scaffold to favour interaction between CUL4A and PTEN and promotes the CUL4A-mediated PTEN ubiquitination degradation, and then activates the PI3K/AKT signaling pathway. Based on these results, we plan to verify the effect of HNF1A-AS1 on the metastasis of GC in vivo, clarify the effect of HNF1A-AS1 on interaction between CUL4A and PTEN and the regulatory mechanism of HNF1A-AS1/CUL4A/PTEN protein complex on downstream signaling pathway. Moreover, we further determine the key binding sites of HNF1A-AS1 and its binding protein, synthesize small molecule locked nucleic acid into the core binding region of HNF1A-AS1, and then verify its potential value as a target for experimental treatment of gastric cancer. This study is expected to clarify the molecular mechanism of HNF1A-AS1 in promoting gastric cancer metastasis and provides new target for GC treatment and has important clinical significance and scientific value.