lncRNA PDE3A/IP3R通路对胃癌侵袭转移的促进作用及分子机制研究

Gastric cancer is one of the world's highest incidence of malignant tumor, invasion and metastasis is the leading cause of death, but the mechanism remains unclear. Through the lncRNA chips and qRT - PCR screening, our team found high expression of lncRNA PDE3A in gastric cancer, Using clinical pathologic data analysis found that the distant metastasis was significantly positive correlation with lnc PDE3A’s high expression, Inhibition of lnc PDE3A expression can obviously inhibit the invasion and metastasis of gastric cancer cells, further we found that IP3R mRNA raised obviously after inhibit lnc PDE3A by mRNA chip, while the inhibition of IP3R can restore stomach cancer cell metastasis ability, our previous studies have found that IP3R can inhibit the invasion and metastasis of gastric cancer cells, on the basis of established, we proposed that lnc PDE3A may reduce IP3R mRNA through regulating its’ mRNA and then promoting invasion and metastasis of gastric cancer. Our team proposed using RNA Pull - down, immunohistochemical, FISH and other molecular biology experiment, combining cells and animal model research relevant molecular mechanisms, expectations to clarify lnc PDE3A to IP3R mRNA regulation function from the molecules, cells, tissues, and whole animal models established four aspects, provide new theoretical basis for the diagnosis and treatment of gastric cancer invasion and metastasis and therapeutic targets.

胃癌是全球发病率最高的恶性肿瘤之一，侵袭转移是其死亡主要原因，但机制仍不清楚。课题组前期通过长非编码RNA(lncRNA)芯片和qRT-PCR筛选出一条在胃癌中高表达的lncRNA ，即lnc PDE3A，临床病理资料分析发现其与胃癌远处转移显著正相关，下调lnc PDE3A表达明显抑制胃癌细胞侵袭转移，进一步通过mRNA芯片和qRT-PCR发现抑制lnc PDE3A后IP3R mRNA明显上调，而同时抑制IP3R能恢复胃癌细胞侵袭转移能力；课题组前期研究还发现IP3R能够抑制胃癌细胞侵袭转移。据此提出“lnc PDE3A可能通过降解IP3R的mRNA调控胃癌侵袭转移”的假说。本课题拟采用RNA Pull-down、免疫组化、FISH 、动物实验等方法，期望从分子、细胞、组织及整体动物水平阐明lnc PDE3A对IP3R mRNA的调控机制，为胃癌侵袭转移的诊治提供新的理论依据和治疗靶点。

胃癌是我国最常见的恶性肿瘤之一，其发病率及死亡率均位列恶性肿瘤的第二位，并呈逐年上升趋势。癌细胞侵袭转移是造成胃癌死亡的主要原因，但分子机制目前尚未阐明。本研究阐明了IP3R结合蛋白IRBIT可促进胃癌细胞的增殖及转移、侵袭，并且与vimentin、AKT蛋白存在结合，IRBIT的表达受到miR-143的靶向抑制，miR-143可能通过IRBIT影响vimentin等信号蛋白的表达，进而抑制胃癌增殖及侵袭转移的分子调控机制，这丰富了对miR-143抑制胃癌增殖和迁移的认识，并可以为胃癌治疗提供新的理论依据和作用靶点。