LincRNA PART1 抑制胃癌细胞EMT的分子机制及其在胃癌转移中的作用

LincRNAs play an important role in the regulation of EMT and tumor metastasis. In our previous work, we identified 7 lncRNAs that were differentially expressed in gastric cancer by GEO database reanalysis. PART1 was identified as significant down-regulated lincRNA in gastric cancer tissues, and its low expression was correlated with the postoperative metastasis and short overall survival time of patients. Overexpression of PART1 could inhibit the TGF-β/Smad signaling pathway and mediated EMT of MCG-803 cells, and decreased cell growth, clone formation, migration and invasion, tumorigenisis and tumor metastasis. The interference of PART1 expression can significantly promote not only TGF-β/Smad signaling pathway and EMT phenotype of AGS cells, but also the cell malignant biological behavior, including growth and metastasis of gastric cancer cells. PART1 can be combined with tumor associated proteins, such as eEF1A, ATP5B, RPL5 and PCNA, which play a key role in the regulation of EMT and EMT-mediated metastasis in gastric cancer cells. On the basis of these findings, in this study, the role of PART1 in the regulation of EMT induced metastasis and the regulation mechanism of PART1 expression were further determined, to provide a clue for prognosis and treatment of gastric cancer.

LincRNAs在EMT转化及肿瘤迁移侵袭过程中起重要调控作用。前期通过GEO数据库外显子测序结果ncRNA注释二次分析，共获得胃癌差异表达7个lincRNAs，其中PART1在胃癌组织中表达显著下调，其低表达与胃癌术后远处转移及总生存期较短相关。PART1过表达后能抑制MCG-803细胞TGF-β/Smad信号通路及其介导的EMT转化，并使细胞体外生长、克隆形成、迁移侵袭、体内致瘤和转移能力下降。而干扰PART1表达则明显促进AGS细胞TGF-β/Smad信号通路及细胞EMT表型、促进胃癌细胞生长和转移等恶性生物学行为。PART1可以与eEF1A、ATP5B、RPL5和PCNA等肿瘤相关蛋白分子结合，发挥对胃癌细胞EMT转化及胃癌转移的调控作用。本研究拟在这些工作基础上，深入探讨PART1在调控EMT诱导胃癌转移中的作用和调变机制及PART1自身表达调控因素，为胃癌预后和治疗提供依据。

前期通过GEO数据库外显子测序分析获得胃癌差异表达7个lincRNAs，PART1因其高差异背书而被选择作进一步研究。PART1在某些癌症中发挥抑癌基因功能，而在其他癌症中则表现为致癌基因功能。在胃癌中，虽有报道其表达下调，PART1在胃癌中的临床意义及作用机制尚不清楚。本研究重点探讨了PART1在胃癌中的临床意义，分子作用及机制。在我们的胃癌验证队列中，通过qPCR和原位杂交鉴定PART1是胃癌组织中lncRNA显著下调，其低表达与术后转移和术后总生存时间短显著相关。通过功能获得实验的结果证实PART1是一种肿瘤抑制因子，不仅在体外能降低细胞活力、迁移和侵袭，在体内也能降低肿瘤的发生和转移。RNA-pulldown和RNA结合蛋白免疫沉淀(RIP)表明PART1与雄激素受体(AR)相互作用，继而上调表达早幼粒细胞白血病锌指(PLZF)。染色质免疫沉淀(ChIP)实验进一步表明，PLZF上调增加了血小板衍生生长因子(PDGFB)启动子中Ezh2和H3K27m3的富集，从而抑制PDGFB/PDGFRβ/PI3K/Akt信号通路。以上结果表明PART1通过促进PLZF的表达，然后招募Ezh2来介导表观遗传PDGFB沉默和下游PI3K/Akt抑制，从而发挥抑制肿瘤的作用。提示PART1在抑制胃癌细胞侵袭能力方面具有关键作用，为lincRNA在胃癌进展中的作用提供了新的视角。