长链非编码RNA PRL-3-AS介导胃癌基因PRL-3的选择性启动子激活的 分子机制研究

PRL-3与癌转移密切相关，之前我们证实PRL-3在胃癌中过表达并通过PI3K通路促进胃癌腹膜转移，但导致胃癌中PRL-3过表达的转录调控机制尚不清楚。近来我们发现PRL-3促癌蛋白亚型存在拥有独立启动子的两个转录本，其中PTP4A3-201的启动子恒定活化，而PTP4A3-001的仅在胃癌中被激活，其激活与启动子甲基化和反义lncRNA PRL-3-AS具有关联性；初步预测PRL-3-AS可结合甲基化相关酶和改变PTP4A3-001而非201表达。由此建立了PRL-3-AS结合并招募甲基化酶到PTP4A3-001的启动子区并进而诱导甲基化改变和转录激活的假说。为此本研究拟先证实胃癌中PRL-3的高表达由PTP4A3-001而非201的启动子甲基化改变导致，进一步证实PRL-3-AS结合甲基化酶到PTP4A3-001的启动子区是导致甲基化改变的深层机制。本研究将为胃癌转移提供新的治疗靶点。

PRL-3 is closely related to tumor metastasis. We have previously confirmed that PRL-3 is overexpressed in gastric cancer and promotes the peritoneal metastasis of gastric cancer through PI3K/Akt signaling pathway. However, the transcriptional regulation mechanism of PRL-3 high expression in gastric cancer is unknown. In the preliminary experiment, we found that PRL-3 oncoprotein have two transcripts subtype with independent promoter, in which PTP4A3-201 promoter constantly activate, while the PTP4A3-001 promoter is only activated in gastric cancer, this activation seems to be closely associated with methylation and antisense lncRNA PRL-3-AS. We tentative predict PRL-3 may bind to the methylated enzymes and regulate the PTP4A3-001 expression but not the PTP4A3-201 expression. We hypothesized that PRL-3-AS binds and recruits the methylated enzymes to the promoter region of PTP4A3-001 to induce methylation to determine the activity of the promoter. Firstly, in this study, we hope to confirme that the high expression of PRL-3 in gastric cancer is induced by the activation of PTP4A3-001 promoter methylation but not the PTP4A3-201. Secondly, we will make further investigation that PRL-3-AS may cobimned with methylase to PTP4A3-001 promoter region which is the main mechanism leading to methylation alteration. The results of this study will provide a new therapeutic target for gastric cancer metastasis.