ARHI与Paxillin相互作用抑制FAK自磷酸化对胃癌细胞恶性表型的影响及机制研究

There are almost 50 percent of gastric cancer patients of the world in China. In recent several decades, although the incidence of gastric cancer generally shows a declining trend all over the world, the majority of patients are diagnosed in an advanced stage, which results in the overall survival of patients with advanced gastric cancer is less than one year. Therefore, there is still important significance to further reveal the molecular mechanism of gastric cancer. Our preliminary study results show that the malignant phenotype of gastric cancer can be inhibited by the tumor suppressor gene ARHI, and the effect is probably through inhibiting FAK autophosphorylation by the interaction of ARHI and Paxillin. Based on our previous results, the present project will elucidate the causal relationship between ARHI-inhibited gastric cancer cell malignant phenotype and FAK autophosphorylation, confirm the interaction sites between ARHI and Paxillin, clarify downstream signaling pathways mediated by FAK in ARHI-inhibited gastric cancer cells, and reveal the relation between ARHI expression, FAK autophosphorylation, the interaction of ARHI and Paxillin and clinical indexes such as the degree of tumor differentiation, TNM staging, metastasis status in gastric cancer tissue samples. We hope that by the implementation of the project, the mechanisms and roles of ARHI in gastric cancer development can be revealed and the experimental basis for its clinical application can be established.

我国胃癌患者几乎占全球一半左右。虽然近几十年来全球胃癌发病率总体上呈下降趋势，但多数患者确诊时已是晚期，而晚期患者的总体生存期不足一年。因此，深入揭示胃癌发病的分子机制依然具有重要意义。我们前期研究结果表明抑癌基因ARHI能够抑制胃癌细胞的恶性表型，其作用可能是通过结合Paxillin进而抑制FAK的自磷酸化而实现的。本项目拟在此基础上，阐明ARHI抑制胃癌细胞的作用和FAK自磷酸化之间的相关性，明确ARHI和Paxillin之间的相互作用位点，分析ARHI结合Paxillin抑制FAK自磷酸化遏制胃癌细胞恶性表型的下游信号通路，揭示胃癌组织样本中ARHI表达水平、ARHI和Paxillin的相互作用、FAK自磷酸化水平与胃癌的分化程度、TNM分期、转移状况等临床指标的相关性。期望通过本项目的实施，能够进一步揭示ARHI在胃癌发展中的作用和机制，为其临床应用奠定实验依据。

我国胃癌患者数量庞大，且多数患者确诊时已是晚期，总体生存期不足一年。因此，深入揭示胃癌发病的分子机制依然具有重要意义。ARHI属于Ras基因超家族，是一种抑癌基因，在多种肿瘤组织中低表达，过表达ARHI能够抑制多种肿瘤细胞的恶性表型。我们前期研究结果表明抑癌基因ARHI能够抑制胃癌细胞的恶性表型，其作用可能是通过结合Paxillin进而抑制FAK的磷酸化而实现的。本项目在此基础上，进一步研究发现过表达ARHI可降低胃癌细胞中FAK和AKT的磷酸化水平，抑制胃癌细胞的侵袭及增殖，而干涉ARHI可促进胃癌细胞的侵袭和增殖，同时发现过表达ARHI抑制了FAK/CREB通路，该通路参与了ARHI对胃癌细胞增殖、迁移的抑制作用，还发现ARHI能够通过Paxillin抑制FAK在粘着斑的聚集，从而抑制其活化。通过本项目的实施，进一步揭示了ARHI抑制胃癌恶性表型的分子机制，为其临床应用奠定实验基础。