Department of General, Visceral, and Transplantation Surgery, Ruprecht-Karls University, Heidelberg, Germany.
Cell Death Dis. 2019 Mar 8;10(3):231. doi: 10.1038/s41419-019-1460-1.
Clinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken from patients with intrahepatic (iCC) and perihilar cholangiocarcinoma (pCC), who underwent liver resection, were analyzed. The relationship of clinicopathological features and c-MET, as well as c-jun N-terminal kinase (JNK) was evaluated. The anti-tumor effects of Tivantinib, a small-molecule inhibitor with potent activity against the c-MET kinase, was investigated in three human CC cell lines, namely HUCC-T1, TFK-1, and EGI-1. In comparison with the results obtained in non-tumor tissue samples, c-MET was overexpressed in 91.3 % of tumor tissues (p < 0.01). The JNK expression was higher in tumor tissue compared with the corresponding non-tumor tissue sample in 17.4% patients (p < 0.01). The inhibition of aberrant c-MET expression in human CC cell lines was achieved by blocking the phosphorylation of c-MET with Tivantinib. Notable losses in cell viability and colony-forming capability were detected (p < 0.01). Synergistic activation of the JNK/c-jun pathway was demonstrated after Tivantinib treatment. Knockdown of the JNK by siRNA or competitive binding of c-MET receptor by stimulation with HGF-antagonized anti-tumor effects of Tivantinib was observed. Our data suggest that inhibition of c-MET could be a possible alternative approach for the treatment of human CC, for which Tivantinib may an effective inhibitor. The synergistic activation of the JNK/c-jun pathway contributed to the elevated apoptosis in CC cells via treatment with Tivantinib.
人胆管癌 (CC) 的临床治疗选择有限。c-MET 是肝细胞生长因子 (HGF) 的高亲和力受体，在许多癌症中失调。其在胆管癌发生中的作用尚不清楚。在目前的研究中，对 23 例接受肝切除术的肝内 (iCC) 和肝门部胆管癌 (pCC) 患者的相应肿瘤和非肿瘤组织进行了分析。评估了 c-MET 与 c-jun N-末端激酶 (JNK) 之间的临床病理特征的关系。研究了一种小分子抑制剂 Tivantinib 对三种人胆管癌细胞系 HUCC-T1、TFK-1 和 EGI-1 的抗肿瘤作用，该抑制剂对 c-MET 激酶具有很强的活性。与非肿瘤组织样本相比，91.3%的肿瘤组织中 c-MET 过度表达（p<0.01）。在 17.4%的患者中，肿瘤组织中 JNK 的表达高于相应的非肿瘤组织样本（p<0.01）。用 Tivantinib 阻断 c-MET 的磷酸化，可抑制人胆管癌细胞系中异常的 c-MET 表达。检测到细胞活力和集落形成能力明显下降（p<0.01）。在用 Tivantinib 处理后，观察到 JNK/c-jun 通路的协同激活。用 siRNA 敲低 JNK 或用 HGF 拮抗剂刺激竞争性结合 c-MET 受体，观察到 Tivantinib 的抗肿瘤作用减弱。我们的数据表明，抑制 c-MET 可能是治疗人胆管癌的一种可行方法，而 Tivantinib 可能是一种有效的抑制剂。JNK/c-jun 通路的协同激活通过用 Tivantinib 处理促进 CC 细胞凋亡。
