LncRNA PCAT1靶向EGFR信号通路调控肺癌增殖侵袭及表观遗传机制

The goal of this application is to investigate the role of EGFR-associated lncRNAs in cancer. As master gene regulators, lncRNAs impact diverse cancer cellular pathways in many types of human cancers. Recently, we found that lncRNA GAS5 can effect as "competing endogenous RNA" (ceRNA) with miR-21, and another lncRNA Loc285194 works depending on P53.Of considerable interest, our preliminary studies suggest that lncRNAs pathways interconnect with the EGFR pathway, forming the lncRNA-EGFR regulatory network. Therefore, a better understanding of this lncRNA-EGFR regulatory network is critical to successful targeting of the EGFR pathway for cancer therapy. We propose three specific aims in this application. The first aim will focus on the regulation of PCAT1, to explore its interaction with EGFR complex. We will determine the underlying mechanism of PCAT1 regulation, and will determine how PCAT1 is upregulated in tumors. Aim 2 is to dissect the molecular pathway of PCAT1-mediated EGFR activation. Specifically, we will determine how PCAT1 induces EGFR activity and dissect molecular and cellular events of EGFR - mediated resistance to gefitinib. The third aim is to determine the clinical significance of PCAT1. We will determine whether there is any correlation between PCAT1 and clinic-pathologic features such as disease stage, metastasis status or other features; We will also determine whether PCAT1 can be a tumor marker and even a new target of tumor molecular therapy. Together, the proposed work will provide a better understanding of EGFR-associated lncRNAs and the underlying mechanism of gene regulation, leading to tumor initiation, progression and gefitinib resistance.

研究表明长链非编码RNAs(LncRNAs)可经多种途径调控肿瘤。我们研究发现lncRNA GAS5与miR-21通过竞争内源性抑制RNA（ceRNA）机制作用,还发现lncRNA Loc285194是P53依赖性抑癌基因。而应用RNA测序及RNA-蛋白免疫共沉淀（RIP）筛查发现：lncRNA PCAT1能够靶定EGFR复合物调控EGFR通路，形成潜在的lncRNA-EGFR调控网络，调节肺癌增殖侵袭。基于此，本研究拟通过对PCAT1靶定EGFR的调节及活化EGFR通路的分子机制、临床资料的研究，完成如下目标：一.明确PCAT1靶定EGFR复合物的特定靶点及方式。二.PCAT1活化EGFR通路对细胞分子水平的影响及表观遗传机制。三.PCAT1对肺癌的临床意义。并探讨PCAT1在如下方面可行性：1.新的肿瘤标记物？2.作为临床靶向治疗及耐药的评价指标？3.针对EGFR通路靶向治疗的新靶点？

长链非编码RNAs(LncRNAs)可经多种途径参与基因调控，包括对肿瘤的调控。我们前期发现lncRNA 可通过竞争内源性抑制RNA（ceRNA）机制作用,还发现lncRNA Loc285194是P53依赖性抑癌基因。应用RNA测序及RNA-蛋白免疫共沉淀筛查发现：lncRNA PCAT1能够靶向EGFR复合物调控EGFR通路，形成潜在的lncRNA-EGFR调控网络，调节肺癌增殖侵袭。基于上述研究背景，本项目针对对PCAT1靶向EGFR的调节及活化EGFR通路的分子机制、临床资料的研究。研究内容包括明确PCAT1靶向结合EGFR复合物的特定靶点和方式，PCAT1对EGFR通路的调控研究并分析其作用机制，以及探讨PCAT1对肺癌的临床评价及临床意义等。项目研究结果表明LncRNA PCAT1能够通过靶向EGFR复合物并参与调控EGFR 下游信号通路发挥作用。同时也表明LncRNA PCAT1是一类潜在的致癌基因，并可能在EGFR-TKIs介导的肿瘤增殖侵袭机制中发挥作用。 项目如期完成如下目标：1.初步明确PCAT1靶定EGFR复合物的特定靶点及方式。2.探讨了PCAT1活化EGFR 通路对细胞分子水平的影响及表观遗传机制。3.探讨了PCAT1对肺癌的临床意义，表明LncRNA PCAT1靶向EGFR通路可能是导致临床靶向治疗无效或耐药的潜在机制。项目初步表明PCAT1在如下方面具有一定的潜力和可行性：1.作为新的肺癌预后标记物；2.作为临床肺癌靶向治疗及耐药的评价指标；3.针对 EGFR通路靶向肺癌治疗的新靶点。