SDF-1/CXCR4信号通路在血小板促进肝癌射频消融后残留癌发生上皮间充质转化中的作用机制

The rapid progression of residual hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) is the current medical challenge. Platelet-derived factors could promote cancer cell proliferation and metastasis. The previous data showed that RFA promoted the release of P-selectin and SDF-1 of platelets in HCC patients. Platelets is the major source of plasma SDF-1. The activated platelets promoted the epithelial mesenchymal transition (EMT) of HCC cells. The expression of CXCR4 was up-regulated in residual tumor after RFA. Based on currently available evidence we put forward the hypothesis that platelets could promote the EMT of residual HCC after RFA and SDF-1/CXCR4 axis plays an important role in the process. The present study was designed to verify the hypothesis by the following steps. The HCC cells are treated with platelets before or after RFA via neutralizing the level of SDF-1, knocking down the expression of CXCR4 or inhibiting receptor-ligand binding by AMD3100. The morphology and activation of platelets, the abilities of adhesion and aggregation of platelets, morphology, proliferation, migration, EMT markers, the phosphorylation level of Akt or ERK, growth and metastasis of HCC cells are investigated. We also establish the model of residual HCC after RFA using PF4CreSDF-1f/f mice, which are treated with SDF-1 neutralizing antibody or rSDF-1. Moreover, the growth and metastasis of residual tumor are investigated. If the hypothesis is verified, the target for the prevention and treatment of progression of residual HCC after RFA would be further enriched.

肝细胞癌（HCC）射频消融（RFA）后残留癌可发生快速进展，血小板可通过释放多种细胞因子促进肿瘤生长和转移。前期发现：RFA后HCC患者血小板P-selectin、SDF-1释放增加，是血浆SDF-1主要来源；激活的血小板促进HCC细胞发生EMT；RFA后HCC残留癌CXCR4表达升高。提出：SDF-1/CXCR4信号通路在血小板促进HCC RFA后残留癌EMT中发挥重要作用。本研究将RFA前后的血小板与HCC细胞作用，通过抗体中和SDF-1、敲低CXCR4表达和应用AMD3100抑制二者结合，观察血小板形态、粘附与聚集，HCC细胞形态、增殖、侵袭、EMT指标、Akt和ERK磷酸化水平以及体内生长、转移能力；建立PF4CreSDF-1f/f小鼠肝癌RFA后残留癌模型，观察SDF-1抗体或rSDF-1处理后残留癌局部生长和转移。该假说如获证实，将丰富HCC RFA后残留癌快速进展的防治靶点。

肝细胞癌（HCC）射频消融（RFA）后残留癌可发生快速进展，血小板可通过释放多种细胞因子促进肿瘤生长和转移。本研究将RFA前后的血小板与HCC细胞作用，通过抗体中和SDF-1、敲低CXCR4表达和应用AMD3100抑制二者结合，并建立小鼠肝癌RFA后残留癌模型，观察血小板形态、粘附与聚集，HCC细胞形态、增殖、侵袭、EMT指标、Akt和ERK磷酸化水平以及体内生长、转移能力。证实RFA后HCC患者血小板激活，其P-selectin、SDF-1释放增加，激活的血小板促进HCC细胞发生EMT；RFA后HCC残留癌CXCR4表达升高，其中SDF-1/CXCR4信号通路在血小板促进HCC RFA后残留癌EMT中发挥重要作用。本研究完善和丰富了HCC RFA后残留癌快速进展的防治靶点。