嘌呤受体P2X4重编程癌成纤维细胞和肿瘤细胞促进肝细胞癌转移研究

肝细胞癌转移的关键是肿瘤细胞上皮细胞间充质转化（EMT），EMT受肿瘤细胞自身改变和微环境中肿瘤成纤维细胞（CAF）调控。肿瘤细胞的反复生长和死亡过程，肿瘤组织周围富含高浓度嘌呤核苷酸。然而肿瘤微环境中高浓度的嘌呤核苷酸和嘌呤受体对肿瘤转移的作用未见报道。本项目实验发现肝细胞癌患者肿瘤细胞和CAF均高表达嘌呤受体P2X4，且与肝细胞癌转移相关；在肝癌细胞中敲除P2X4可抑制EMT并显著降低细胞迁移能力，CAF高表达P2X4亦可促进肝癌细胞EMT，且二者均与P2X4介导的YAP/TAZ信号通路有关。鉴此，本项目提出假设即肿瘤微环境中高浓度的嘌呤核苷酸与P2X4受体的频繁作用可能是肿瘤转移的重要原因。本项目拟以P2X4为切入点系统研究和明确P2X4与肝癌转移的相关性；揭示P2X4重编程CAF和肿瘤细胞促进肝癌转移的作用及机制；探索形成靶向P2X4为核心干预肝癌转移的治疗新策略。

Epithelial mesenchymal transformation (EMT) is a key step to primary hepatocellular carcinoma metastasis. EMT is regulated by tumor cells and tumor fibroblasts (CAF) in the microenvironment.The tumor microenvironment is rich in high concentrations of purine nucleotides due to process of repeated growth and death of tumor cells. However, the effect of high concentration of purine nucleotides and purine receptors in tumor microenvironment on tumor metastasis has not been reported.In preliminary experiments of this project, we found that both tumor cells and CAF of patients with hepatocellular carcinoma were highly expressed with purine receptor P2X4, which was associated with hepatocellular carcinoma metastasis. Interestingly, Knockdown of P2X4 in HCC cells can inhibit EMT and significantly reduce cell migration, while high expression of P2X4 in CAF can also promote HCC cells EMT, both of which are related to the P2X4 mediated Hippo-YAP/TAZ signaling pathway. In this context, the scientific question of this project focuses on the mechanism by which the purine receptor P2X4 regulates the EMT by the YAP/TAZ pathway between CAF and tumor cells in HCC metastasis. We intend to systematically study and clarify the correlation between P2X4 and the clinicopathological features of HCC metastasis. We try to clarify the regulatory role of P2X4 in liver cancer metastasis. Furthermore, we will elucidate the molecular mechanism of p2x4-mediated Hippo-YAP/TAZ signaling pathway promoting EMT in tumor cells and CAF. Finally, we could explore a new therapeutic strategy of targeting P2X4 for liver cancer metastasis.