Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
J Cell Mol Med. 2016 May;20(5):825-35. doi: 10.1111/jcmm.12808. Epub 2016 Mar 1.
S100A4, a member of the S100 protein family of EF-hand calcium-binding proteins, is overexpressed in various tumour entities, including melanoma, and plays an important role in tumour progression. Several studies in epithelial and mesenchymal tumours revealed a correlation between extracellular S100A4 and metastasis. However, exact mechanisms how S100A4 stimulates metastasis in melanoma are still unknown. From a pilot experiment on baseline synthesis and secretion of S100A4 in human melanoma cell lines, which are in broad laboratory use, A375 wild-type cells and, additionally, newly generated A375 cell lines stably transfected with human S100A4 (A375-hS100A4) or human receptor for advanced glycation endproducts (A375-hRAGE), were selected to investigate the influence of extracellular S100A4 on cell motility, adhesion, migration and invasion in more detail. We demonstrated that A375 cells actively secrete S100A4 in the extracellular space via an endoplasmic reticulum-Golgi-dependent pathway. S100A4 overexpression and secretion resulted in prometastatic activation of A375 cells. Moreover, we determined the influence of S100A4-RAGE interaction and its blockade on A375, A375-hS100A4, A375-hRAGE cells, and showed that interaction of RAGE with extracellular S100A4 contributes to the observed activation of A375 cells. This investigation reveals additional molecular targets for therapeutic approaches aiming at blockade of ligand binding to RAGE or RAGE signalling to inhibit melanoma metastasis.
S100A4 是 S100 蛋白家族 EF 手钙离子结合蛋白的成员，在包括黑色素瘤在内的各种肿瘤实体中过表达，并在肿瘤进展中发挥重要作用。上皮和间充质肿瘤的几项研究表明，细胞外 S100A4 与转移之间存在相关性。然而，S100A4 如何刺激黑色素瘤转移的确切机制仍不清楚。从人类黑色素瘤细胞系中 S100A4 基础合成和分泌的初步实验中，选择 A375 野生型细胞，以及新生成的稳定转染人 S100A4（A375-hS100A4）或人晚期糖基化终产物受体（A375-hRAGE）的 A375 细胞系，以更详细地研究细胞外 S100A4 对细胞迁移、黏附、迁移和侵袭的影响。我们证明 A375 细胞通过内质网-高尔基体依赖性途径主动将 S100A4 分泌到细胞外空间。S100A4 的过表达和分泌导致 A375 细胞的促转移激活。此外，我们确定了 S100A4-RAGE 相互作用及其阻断对 A375、A375-hS100A4、A375-hRAGE 细胞的影响，并表明 RAGE 与细胞外 S100A4 的相互作用有助于观察到 A375 细胞的激活。这项研究揭示了针对旨在阻断配体与 RAGE 结合或抑制 RAGE 信号以抑制黑色素瘤转移的治疗方法的其他分子靶标。
