Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, "Sapienza" University of Rome, 00161 Rome, Italy.
Department of Surgery "Pietro Valdoni", "Sapienza" University of Rome, 00161 Rome, Italy.
Int J Mol Sci. 2019 Jan 14;20(2):320. doi: 10.3390/ijms20020320.
c-MET pathway over-activation is the signature of malignancy acquisition or chemotherapy resistance of many cancers. We recently demonstrated that type II Testicular Germ Cell Tumours (TGCTs) express c-MET receptor. In particular, we elucidated that the non-seminoma lesions express c-MET protein at higher level, compared with the seminoma ones. In line with this observation, NTERA-2 clone D1 (NT2D1) non-seminoma cells increase their proliferation, migration and invasion in response to Hepatocyte Growth Factor (HGF). One of the well-known adaptor-proteins belonging to c-MET signaling cascade is c-Src. Activation of c-Src is related to the increase of aggressiveness of many cancers. For this reason, we focused on the role of c-Src in c-MET-triggered and HGF-dependent NT2D1 cell activities. In the present paper, we have elucidated that this adaptor-protein is involved in HGF-dependent NT2D1 cell proliferation, migration and invasion, since Src inhibitor-1 administration abrogates these responses. Despite these biological evidences western blot analyses have not revealed the increase of c-Src activation because of HGF administration. However, notably, immunofluorescence analyses revealed that cytoplasmic and membrane-associated localization of c-Src shifted to the nuclear compartment after HGF stimulation. These results shed new light in the modality of HGF-dependent c-Src recruitment, and put the basis for novel investigations on the relationship between c-Src, and TGCT aggressiveness.
c-MET 通路的过度激活是许多癌症获得恶性表型或化疗耐药的特征。我们最近证实，II 型睾丸生殖细胞肿瘤（TGCTs）表达 c-MET 受体。特别是，我们阐明了非精原细胞瘤病变比精原细胞瘤表达更高水平的 c-MET 蛋白。与此观察结果一致，NTERA-2 克隆 D1（NT2D1）非精原细胞瘤细胞在应对肝细胞生长因子（HGF）时增加其增殖、迁移和侵袭。属于 c-MET 信号级联的众所周知的衔接蛋白之一是 c-Src。c-Src 的激活与许多癌症侵袭性的增加有关。出于这个原因，我们专注于 c-Src 在 c-MET 触发和 HGF 依赖性 NT2D1 细胞活性中的作用。在本文中，我们阐明了这种衔接蛋白参与 HGF 依赖性 NT2D1 细胞增殖、迁移和侵袭，因为 Src 抑制剂-1 的给药会消除这些反应。尽管有这些生物学证据，但 Western blot 分析并未显示出由于 HGF 给药而导致 c-Src 激活增加。然而，值得注意的是，免疫荧光分析显示，HGF 刺激后 c-Src 的细胞质和膜相关定位转移到核区室。这些结果为 HGF 依赖性 c-Src 募集的方式提供了新的见解，并为研究 c-Src 与 TGCT 侵袭性之间的关系奠定了基础。
