Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma
Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma
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DOI：
10.1158/0008-5472.can-04-4567
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Salgia, R
中科院分区：
文献类型：
--
作者：
Jagadeeswaran, R;Ma, PC;Salgia, R
c-Met受体酪氨酸激酶（RTK）尚未在恶性胸膜间皮瘤（MPM）中进行广泛研究。在这项研究中，c-Met在大多数测试的间皮瘤细胞系中过表达和活化。免疫组化显示MPM组织中的表达与正常组织相比普遍增加（82%）。在H28 MPM细胞中，c-Met与其配体肝细胞生长因子（HGF）一起内化，具有c-Met的稳健表达。间皮瘤患者的血清循环HGF是健康对照组的两倍。有一个不同的生长反应和激活AKT和细胞外信号调节激酶1/2的各种细胞系响应HGF。小分子c-Met抑制剂SU 11274对间皮瘤细胞系的细胞生长具有剂量依赖性抑制作用（IC 50 < 2.5 μ mol/L），但对H2052、H2452和非恶性MeT-5A细胞生长无抑制作用（IC 50> 10 μ mol/L）。此外，SU 11274和c-Met小干扰RNA均阻断了H28细胞的迁移。在间皮瘤细胞中观察到HGF诱导的c-Met和下游信号传导的消除。在43个MPM组织和7个细胞系中，我们已经确定了脑信号蛋白结构域（N375 S，M431 V和N454 I），跨膜结构域（T1010 I和G1085 X）内的突变，以及在一些样品中c-Met的外显子10缺失的可变剪接产物。有趣的是，我们观察到，与野生型1128和非恶性MeT-5A细胞相比，携带T1010 I突变的细胞系H513和H2596在SU 11274的作用下表现出最显著的细胞生长减少。最终，c-Met将成为MPNI治疗的重要靶点。
c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 mu mol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 > 10 mu mol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtarnembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type 1128 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPNI.