Thrombin is a Therapeutic Target for Metastatic Osteopontin-Positive Hepatocellular Carcinoma
Thrombin is a Therapeutic Target for Metastatic Osteopontin-Positive Hepatocellular Carcinoma
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DOI：
10.1002/hep.23942
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发表时间：
2010-12-01
期刊：
影响因子：
13.5
通讯作者：
Qin, Lun-Xiu
中科院分区：
文献类型：
--
作者：
Xue, Yu-Hua;Zhang, Xiao-Fei;Qin, Lun-Xiu
我们以前鉴定骨桥蛋白（OPN）作为启动子，因此是肝细胞癌（HCC）转移的潜在治疗靶点。丝氨酸蛋白酶凝血酶与OPN相互作用，并可以改变其生物活性。为了探索凝血酶单独或与OPN联合在HCC中的作用，我们研究了凝血酶水平与具有不同OPN水平的患者的HCC预后的相关性，并评估了凝血酶裂解产生的OPN片段对HCC细胞增殖和粘附的影响。我们发现凝血酶水平与HCC细胞系的转移潜能密切相关，并且与邻近的非肿瘤组织相比，凝血酶在HCC组织中显著过表达。此外，复发患者的HCC组织显示出更高的凝血酶水平，特别是在OPN水平升高的患者中。只有OPN水平升高的HCC患者的凝血酶水平与总生存率之间存在显著相关性。（OS，P <001）或至复发时间（TTR，P <0.0001）多变量分析显示凝血酶是一个独立的预后指标。体外实验表明凝血酶促进肝癌细胞的增殖和粘附。结论凝血酶通过激活整合素β 1-FAK信号通路，在OPN介导的HCC侵袭表型中起重要作用，是HCC的独立预后不良因子。凝血酶可能是抑制OPN +患者HCC转移的潜在治疗靶点（HEPATOLOGY 2010，52 2012-2022）
We previously identified osteopontin (OPN) as a promoter and thus a potential therapeutic target for hepatocellular carcinoma (HCC) metastasis The serine protease thrombin interacts with OPN and can modify its biological activity To explore the role of thrombin alone or in conjunction with OPN in HCC, we studied the correlation of thrombin levels to HCC prognosis in patients with various OPN levels, and evaluated the effects of OPN fragments generated by thrombin cleavage on proliferation and adhesion of HCC cells We found that the thrombin level was strongly associated with the metastatic potential of HCC cell lines, and that thrombin was remarkably overexpressed in HCC tissue compared with adjacent nontumor tissue In addition, HCC tissue from patients with recurrent disease displayed much higher thrombin levels, particularly in those with elevated OPN levels Only HCCs with elevated OPN levels had a significant correlation between high thrombin levels and overall survival (OS, P < 0 01), or time to recurrence (TTR, P < 0 0001) of HCC Multivariate analysis revealed that thrombin was an independent prognostic indicator In vitro assays demonstrated that thrombin promotes the proliferation and adhesion of OPN + HCC cells Furthermore, thrombin activated the focal adhesion kinase (FAK) pathway of OPN + HCC cells, which was blocked by the inhibition of mtegrin beta 1 Conclusion Thrombin plays an important role in OPN-mediated aggressive phenotype of HCC through activation of integrin beta 1-FAK signaling, and Is an independent poor prognostic factor for HCC Thus, thrombin may be a potential therapeutic target to inhibit HCC metastasis in OPN + patients (HEPATOLOGY 2010,52 2012-2022)