H.pylori CagA+上调Na+/Ca2+交换器1促进胃癌侵袭的分子机制研究

侵袭转移是胃癌患者死亡的重要原因，而作为胃癌I类致癌因子的幽门螺旋杆菌（H.pylori）不仅在胃癌发生中具有重要作用，而且参与了胃癌的侵袭转移。已知细胞内Ca2+信号异常与癌症的侵袭转移密切相关，但仍不清楚H.pylori感染可否通过调控Ca2+信号促进胃癌细胞的侵袭。我们前期预实验发现，H.pylori中的CagA蛋白可通过胃癌细胞膜上的Na+/Ca2+交换器1（NCX1）介导细胞外Ca2+内流，促进胃癌的侵袭转移；文献报道CagA可激活IkB，促使NF-kBp65入核增加，我们预测发现p65可与NCX1启动子结合，增强其转录活性，进而上调NCX1的表达，增加胞内Ca2+信号。据此我们推测“H.pylori通过CagA/NF-kBp65通路上调NCX1/Ca2+信号，促进胃癌侵袭”。本课题拟通过现代生理学和分子生物学技术阐明以上假说，以期为胃癌的早期诊治提供新的策略。

Invasion and metastasis are important causes of death in patients with gastric cancer, and Helicobacter pylori (H.pylori), as a class I carcinogenic factor of gastric cancer, not only plays an important role in the occurrence of gastric cancer, but also participates in the invasion and metastasis of gastric cancer. It is known that abnormal intracellular Ca2+ signaling is closely related to the invasion and metastasis of cancer, but it is still unclear whether H.pylori infection can promote the invasion of gastric cancer cells by regulating Ca2+ signaling. Our preliminary experiments showed that the secretory effector protein CagA in H.pylori mediated extracellular Ca2+ influx through the Na+/Ca2+ exchanger 1 (NCX1) on the cell membrane of gastric cancer and promoted the invasion and metastasis of gastric cancer. It has been reported that CagA activates IkB and promotes the nucleation increase of NF-kBp65. We predicted that p65 can bind to the NCX1 promoter to enhance its transcriptional activity, thus upregulating the expression of NCX1 and increasing intracellular Ca2+ signal. Therefore, we speculated that "H.pylori upregulated NCX1/Ca2+ signal through CagA/NF-kBp65 pathway to promote gastric cancer invasion". This study intends to clarify the above hypotheses through modern physiology and molecular biology techniques, in order to provide a new strategy for the early diagnosis and treatment of gastric cancer.