Extracellular vesicle-dependent effect of RNA-binding protein IGF2BP1 on melanoma metastasis.
Extracellular vesicle-dependent effect of RNA-binding protein IGF2BP1 on melanoma metastasis.
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DOI：
10.1038/s41388-019-0797-3
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发表时间：
2019-05
期刊：
影响因子：
8
通讯作者：
Spiegelman VS
中科院分区：
文献类型：
--
作者：
Ghoshal A;Rodrigues LC;Gowda CP;Elcheva IA;Liu Z;Abraham T;Spiegelman VS
胰岛素样生长因子2 mRNA结合蛋白1（IGF 2BP 1）是一种多功能的RNA结合蛋白，具有癌胚表达模式，与多种恶性肿瘤的发生有关。在这项研究中，我们探讨了IGF 2BP 1在黑色素瘤发生和进展中的作用和机制。在两种不同的体内模型中，我们发现，虽然IGF 2BP 1的基因缺失或shRNA介导的抑制不影响原发性肿瘤的形成，但它显著抑制了肺转移。在这里，我们证明了黑色素瘤细胞分泌的细胞外囊泡（EV）介导了IGF 2BP 1对转移的影响：来自IGF 2BP 1敲除黑色素瘤细胞的EV未能促进转移，而从IGF 2BP 1过表达的黑色素瘤细胞中分离的EV进一步加速了EV诱导的转移。此外，与对照EV相比，来自IGF 2BP 1敲低黑素瘤细胞的EV抑制肺中纤连蛋白沉积和CD 45+细胞的积累，从而阻断EV的转移前小生境形成潜力。IGF 2BP 1敲低不影响分泌型EV的大小、数量或蛋白/RNA浓度，也不影响其在体外或体内被受体细胞摄取。然而，EV的RNA测序和蛋白质组学分析揭示了许多mRNA、蛋白质和miRNA的差异表达。这表明IGF 2BP 1密切参与EV货物的调节，从而影响黑素瘤衍生的EV的促转移功能。据我们所知，这是第一项证明RNA结合蛋白IGF 2BP 1在EV介导的促进黑色素瘤转移中的作用的研究，并可能为转移抑制剂的开发提供新的途径。
Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is a multifunctional RNA-binding protein with an oncofetal pattern of expression shown to be implicated in the development of a variety of malignancies. In this study, we explored the role and mechanisms of IGF2BP1 in melanoma development and progression. In two different in vivo models, we showed that while genetic deletion or shRNA-mediated suppression of IGF2BP1 did not affect primary tumor formation, it drastically suppressed lung metastasis. Here we demonstrated that extracellular vesicles (EVs) secreted by melanoma cells mediate the effects of IGF2BP1 on metastasis: EVs from the IGF2BP1 knockdown melanoma cells failed to promote metastasis whereas EVs isolated from IGF2BP1-overexpressed melanoma cells further accelerated EV-induced metastasis. Moreover, the EVs from IGF2BP1 knockdown melanoma cells inhibited fibronectin deposition and accumulation of CD45+ cells in the lungs compared to control EVs, thus blocking the pre-metastatic niche formation potential of EVs. IGF2BP1 knockdown did not affect size, number, or protein/RNA concentration of secreted EVs or their uptake by recipient cells in vitro or in vivo. However, RNA-sequencing and proteomics analysis of the EVs revealed differential expression in a number of mRNA, proteins and miRNAs. This suggested that IGF2BP1 is intimately involved in the regulation of the cargo of EVs, thereby affecting the pro-metastatic function of melanoma-derived EVs. To the best of our knowledge, this is the first study that demonstrates the role of RNA-binding protein IGF2BP1 in EV-mediated promotion of melanoma metastasis and may provide novel avenues for the development of metastatic inhibitors.
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