糖蛋白VI介导的肿瘤诱导血小板活化在肝癌中的作用研究

Clinical and experimental evidences support that hepatocellular carcinoma (HCC) patients always come with hyper platelet activity, and activated platelets could promote growth and metastasis of HCC cells. But the underlying mechanisms are poorly understood. Our preliminary data implied that both SMMC.7721 and HepG2 cells could induce platelet aggregation and activate signaling pathway of GPVI-PLCγ2. GPVI monoclone antibody JAQ-1 could abolish this effect. Additionally, JAQ1 countered the promoting proliferation effect of platelet on HCC cells. Moreover, GPVI level was much higher in HCC patients when compared with health human control. Accordingly, we speculate that HCC patients expressed high level of fibrin in plasma, which could combine to GPVI receptor and activate platelets, leading to the promoting effect of platelet on HCC growth and metastasis. Blocking GPVI breaks HCC-induced platelet activation, and might improve HCC progression. We will explore the effect of GPVI in HCC cells-induced platelet activation and tumor progression by using HCC cells with different metastasis capacity and GPVI knockout mice. GPVI expression and platelet activity of HCC patients will also be analyzed. Based on the above study, platelet GPVI may become a new therapeutic targets for prevention and treatment of HCC.

临床和实验研究均提示肝癌患者体内血小板活性增高，活化的血小板能够进一步促进肝癌细胞增殖转移，但其中的作用机理尚不完全清楚。我们前期研究发现肝癌细胞可以诱导血小板聚集，激活血小板GPVI信号通路。而GPVI单克隆抗体JAQ1可完全阻断肝癌细胞诱导血小板聚集的作用，并抑制血小板的促肝癌细胞体外增殖；此外，肝癌患者血小板GPVI表达亦明显高于正常人。据此我们推测：在肝癌进程中，血液循环中纤维蛋白含量升高，激活血小板膜表面GPVI受体，活化血小板，进而促进肝癌增殖转移；通过干预血小板膜受体GPVI，抑制肝癌诱导的血小板活化，可改善肝癌的进程和预后。本课题拟采用不同转移潜能的肝癌细胞、GPVI基因敲除小鼠和肝癌病人样本分析三个层面明确GPVI在肝癌诱导血小板活化中的作用及其对肝癌发生发展的影响。通过以上研究，将从血小板膜受体GPVI这一新视角，为肝癌防治提供新的思路和靶点。

原发性肝细胞癌(简称肝癌，HCC)是全球第二大癌症相关死亡原因，其发病率高，预后差，具有较高的复发和转移风险。随着肿瘤微环境研究的不断深入，我们早期研究发现血小板能够促进肿瘤增殖转移，而血小板及血小板活化已被确定为癌症治疗的潜在新药靶点。但是，肿瘤细胞如何激活血小板，其中的分子机制并不十分清楚。本项目中，我们以肝癌细胞诱导血小板活化为重点研究对象，在细胞和动物水平对血小板膜受体GPVI参与肝癌细胞诱导血小板活化的作用及相关分子机制进行了深入研究，明确了GPVI在肝癌诱导血小板活化中的重要作用，并发现抑制血小板GPVI信号通路能有效抑制肝癌发生发展。我们还发现肝癌患者血小板活性升高，GPVI表达增加且下游信号分子磷酸化增加。此外，我们还通过药物筛选发现血根碱通过靶向血小板GPVI通路抑制胶原诱导的血小板活化和血栓形成，可能成为抗血小板和抗肿瘤相关血栓的有效治疗药物。