SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma
SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma
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DOI：
10.1073/pnas.211026798
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发表时间：
2001-10-09
影响因子：
11.1
通讯作者：
Gaudino, G
中科院分区：
文献类型：
--
作者：
Cacciotti, P;Libener, R;Gaudino, G
最近的研究表明，猿猴病毒40 （SV40）可能引起恶性间皮瘤，但致病机制尚不清楚。我们发现在sv40阳性的恶性间皮瘤细胞中，肝细胞生长因子（HGF）受体（Met）被激活。在转染全长SV40 DNA （SV40-HMC）的人间皮细胞（HMC）中，Met受体的激活与s期进入、成纤维细胞样形态的获得和病毒颗粒的组装有关。共培养实验显示SV40-HMC能够感染允许猴细胞（CV-1）、HMC和小鼠BNL CL细胞。共培养的人和小鼠sv40阳性细胞表达HGF，显示Met酪氨酸磷酸化和s期进入，并获得纺锤形形态（spBNL），而CV-1细胞则被裂解。共培养的HMC继承了SV40-HMC的感染性，因为它们在共培养的CV-1细胞中诱导裂解。用苏拉明或hgf阻断抗体治疗可抑制所有大T抗原（Tag）阳性细胞的Met酪氨酸磷酸化，并恢复spBNL的纺锤形形态。这一发现表明Met激活和随后的生物学效应是由自分泌HGF回路介导的。这反过来又与标签表达有因果关系，仅用SV40早期区域转染即可诱导。我们的研究结果表明，当SV40感染HMC时，它通过自分泌循环引起Met激活。此外，SV40在HMC中复制并感染邻近的HMC，诱导依赖hgf的Met激活和细胞周期进入S期。这可以解释为什么有限数量的sv40阳性细胞足以指导未感染的HMC向恶性转化。
Recent studies suggested that simian virus 40 (SV40) may cause malignant mesothelioma, although the pathogenic mechanism is unclear. We found that in SV40-positive malignant mesothelioma cells, the hepatocyte growth factor (HGF) receptor (Met) was activated. In human mesothelial cells (HMC) transfected with full-length SV40 DNA (SV40-HMC), Met receptor activation was associated with S-phase entry, acquisition of a fibroblastoid morphology, and the assembly of viral particles. Coculture experiments revealed the ability of SV40-HMC to infect permissive monkey cells (CV-1), HMC, and murine BNL CL cells. Cocultured human and murine SV40-positive cells expressed HGF, showed Met tyrosine phosphorylation and S-phase entry, and acquired a spindle-shaped morphology (spBNL), whereas CV-1 cells were lysed. Cocultured HMC inherited from SV40-HMC the infectivity, as they induced lysis in cocultured CV-1 cells. Treatment with suramin or HGF-blocking antibodies inhibited Met tyrosine phosphorylation in all large T antigen (Tag)-positive cells and reverted the spindle-shaped morphology of spBNL. This finding indicated that Met activation and subsequent biological effects were mediated by an autocrine HGF circuit. This, in turn, was causally related to Tag expression, being induced by transfection with the SV40 early region alone. Our findings suggest that when SV40 infects HMC it causes Met activation via an autocrine loop. Furthermore, SV40 replicates in HMC and infects the adjacent HMC, inducing an HGF-dependent Met activation and cell-cycle progression into S phase. This may explain how a limited number of SV40-positive cells may be sufficient to direct noninfected HMC toward malignant transformation.