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IGF2BP1 调节细胞外囊泡的货物运输并促进神经母细胞瘤转移。

IGF2BP1 regulates the cargo of extracellular vesicles and promotes neuroblastoma metastasis.

机构信息

Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, USA.

Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Penn State Cancer Institute, Hershey, PA, USA.

出版信息

Oncogene. 2023 May;42(19):1558-1571. doi: 10.1038/s41388-023-02671-0. Epub 2023 Mar 27.

DOI:10.1038/s41388-023-02671-0
PMID:36973517
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10547097/
Abstract

Neuroblastoma is a highly metastatic cancer, and thus is one of the leading causes of cancer-related mortalities in pediatric patients. More than 50% of NB cases exhibit 17q21-ter partial chromosomal gain, which is independently associated with poor survival, suggesting the clinical importance of genes at this locus in NB. IGF2BP1 is one such proto-oncogene located at 17q locus, and was found to be upregulated in patients with metastatic NBs. Here, utilizing multiple immunocompetent mouse models, along with our newly developed highly metastatic NB cell line, we demonstrate the role of IGF2BP1 in promoting NB metastasis. Importantly, we show the significance of small extracellular vesicles (EVs) in NB progression, and determine the pro-metastatic function of IGF2BP1 by regulating the NB-EV-protein cargo. Through unbiased proteomic analysis of EVs, we discovered two novel targets (SEMA3A and SHMT2) of IGF2BP1, and reveal the mechanism of IGF2BP1 in NB metastasis. We demonstrate that IGF2BP1 directly binds and governs the expression of SEMA3A/SHMT2 in NB cells, thereby modulating their protein levels in NB-EVs. IGF2BP1-affected levels of SEMA3A and SHMT2 in the EVs, regulate the formation of pro-metastatic microenvironment at potential metastatic organs. Finally, higher levels of SEMA3A/SHMT2 proteins in the EVs derived from NB-PDX models indicate the clinical significance of the two proteins and IGF2BP1-SEMA3A/SHMT2 axis in NB metastasis.

摘要

神经母细胞瘤是一种高度转移性癌症，因此是导致儿科患者癌症相关死亡的主要原因之一。超过 50%的 NB 病例表现出 17q21-ter 部分染色体获得，这与不良生存独立相关，表明该基因座的基因在 NB 中具有重要的临床意义。IGF2BP1 是位于 17q 基因座的原癌基因之一，在转移性 NB 患者中发现其上调。在这里，我们利用多种免疫活性小鼠模型，以及我们新开发的高度转移性 NB 细胞系，证明了 IGF2BP1 在促进 NB 转移中的作用。重要的是，我们展示了小细胞外囊泡 (EVs) 在 NB 进展中的重要性，并通过调节 NB-EV-蛋白载物确定了 IGF2BP1 的促转移功能。通过对 EVs 的无偏蛋白组学分析，我们发现了 IGF2BP1 的两个新靶标 (SEMA3A 和 SHMT2)，并揭示了 IGF2BP1 在 NB 转移中的作用机制。我们证明 IGF2BP1 直接结合并调节 NB 细胞中 SEMA3A/SHMT2 的表达，从而调节其在 NB-EVs 中的蛋白水平。IGF2BP1 影响的 SEMA3A 和 SHMT2 水平在 EVs 中，调节潜在转移器官中促转移微环境的形成。最后，来自 NB-PDX 模型的 EVs 中 SEMA3A/SHMT2 蛋白水平较高，表明这两种蛋白和 IGF2BP1-SEMA3A/SHMT2 轴在 NB 转移中的临床意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/045e744d5035/nihms-1932964-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/2411d80fee9c/nihms-1932964-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/045e744d5035/nihms-1932964-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/2411d80fee9c/nihms-1932964-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/70a39827778e/nihms-1932964-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/31acf99e5ab6/nihms-1932964-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c23/10547097/045e744d5035/nihms-1932964-f0006.jpg

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