远处转移相关lncRNA-PSIMCT-1通过CREB磷酸化途径调控胃癌转移的作用机制研究

Distant metastasis is one of the most important factors affecting the prognosis of gastric cancer. Our preliminary data showed that lncRNA-PSIMCT-1 regulated the transcription of HM13 gene through the phosphorylation of its transcription factor CREB. The phosphorylation of CREB might serve as the crucial step. In this study, the expression of lncRNA-PSIMCT-1, CREB and HM13 in gastric cancer tissues and metastatic tissues as well as the relationship between their expression and the clinical pathological parameters will be analyzed; the mechanism of lncRNA-PSIMCT-1 regulating the phosphorylation of CREB as “scaffold” and “molecular decoy” will be investigated; the mechanisms of lncRNA-PSIMCT-1 regulating the total protein expression of CREB through phosphorylation-dependent ubiquitination will be explored;carcinoma oncogeneis model will be used to verify the mechanism of lncRNA-PSIMCT-1 retualting the metastais of gastric cancer through the phosphorylation pathway of CREB. Our study will clarify the mechanism of lncRNA-PSIMCT-1 regulating the metastasis of gastric cancer through the phosphorylation pathway of CREB, which might contribute the new target to the treatment of distant metastasis from gastric cancer.

远处转移是导致胃癌预后差的重要因素。我们前期通过lncRNA（长链非编码RNA）微阵列芯片、生物信息学、功能实验等筛选出lncRNA-PSIMCT-1为胃癌远处转移相关lncRNA,并可能通过调节转录因子CREB的蛋白和磷酸化水平调控靶基因HM13转录。本课题拟在配对胃癌组织及转移灶中分析lncRNA-PSIMCT-1、CREB、HM13等的表达及其与临床病理指标、预后的关系；探索lncRNA-PSIMCT-1通过“脚手架”和“分子诱饵”作用调控CREB磷酸化水平及其转录功能的分子机制；探索lncRNA-PSIMCT-1通过磷酸化依赖的泛素化途径调控CREB总蛋白水平的分子机制；在裸鼠体内对lncRNA-PSIMCT-1通过CREB磷酸化途径调控胃癌转移的分子机制进行验证。旨在阐明lncRNA-PSIMCT-1通过CREB磷酸化途径调节胃癌远处转移的作用机制，为胃癌远处转移治疗提供新靶点。

远处转移是导致胃癌预后差的重要因素。我们通过lncRNA(长链非编码RNA)微阵列 芯片、生物信息学、功能实验等筛选出lncRNA-PSIMCT-1为胃癌远处转移相关lncRNA,并验证其通过调节转录因子CREB的蛋白和磷酸化水平调控靶基因HM13转录。本课题在配对胃癌组织及转移灶中分了lncRNA-PSIMCT-1、CREB、HM13等的表达及其与临床病理指标、预后的关系，发现PSIMCT-1 的表达水平与胃癌患者的年龄、性别、肿瘤大小、分化程度、肿瘤大体类型、局部侵袭深度和淋巴结转移无显著相关，但与胃癌远处转移及临床TNM 分期显著相关，PSIMCT-1 高表达的患者PFS 亦明显短于PSIMCT-1 低表达患者; 进一步明确了lncRNA-PSIMCT-1通过“分子诱饵”作用调控CREB磷酸化水平及其转录功能的分子机制; 并在动物体内验证lncRNA-PSIMCT-1通过CREB磷酸化途径调控胃癌转移的分子机制。本课题阐明了lncRNA-PSIMCT-1通过CREB磷酸化途径调节HM13表达影响胃癌远处转移的作用机制，为胃癌远处转移治疗提供新思路和新靶点。