神经母细胞瘤是儿童中最常见的非颅内实体肿瘤，起源于发育中的交感神经系统神经嵴细胞。前列腺素E2（PGE2）被确认为促进神经母细胞瘤进展的肿瘤微环境（TME）的关键炎性介质。我们报告了微小RNA miR-574-5p与CUG结合蛋白1（CUGBP1）之间的相互作用在神经母细胞瘤细胞中诱导了微粒体前列腺素E2合酶1（mPGES-1）的表达，这有助于PGE2的生物合成。然后，PGE2在神经母细胞瘤细胞系中特异性诱导了miR-574-5p在小型细胞外囊泡（sEV）中的排序。sEV是TME中细胞间通讯的重要角色之一。我们发现sEV来源的miR-574-5p在神经母细胞瘤中具有旁分泌功能。它作为直接的Toll-like受体7/8（TLR7/8）配体，并诱导成纤维细胞中α-平滑肌肌动蛋白（α-SMA）的表达，从而促进了成纤维细胞的分化。这一点尤为值得注意，因为它与另一种依赖于PGE2的肿瘤类型——肺癌TME中的功能相反。在这里，sEV来源的miR-574-5p具有自分泌功能，抑制了肺癌细胞中的PGE2生物合成。我们报告了sEV表面的四跨膜蛋白组成与sEV来源的miR-574-5p功能相关。这表明囊泡不仅可以转运miR，还似乎影响它们的作用方式。版权所有©2023年Proestler，Donzelli，Nevermann，Breitwieser，Koch，Best，Fauth，Wickström，Harter，Kogner，Lavieu，Larsson和Saul。

Neuroblastoma is the most common extracranial solid tumor in childhood and arises from neural crest cells of the developing sympathetic nervous system. Prostaglandin E2 (PGE2) has been identified as a key pro-inflammatory mediator of the tumor microenvironment (TME) that promotes neuroblastoma progression. We report that the interaction between the microRNA miR-574-5p and CUG-binding protein 1 (CUGBP1) induces the expression of microsomal prostaglandin E2 synthase 1 (mPGES-1) in neuroblastoma cells, which contributes to PGE2 biosynthesis. PGE2 in turn specifically induces the sorting of miR-574-5p into small extracellular vesicles (sEV) in neuroblastoma cell lines. sEV are one of the major players in intercellular communication in the TME. We found that sEV-derived miR-574-5p has a paracrine function in neuroblastoma. It acts as a direct Toll-like receptor 7/8 (TLR7/8) ligand and induces α-smooth muscle actin (α-SMA) expression in fibroblasts, contributing to fibroblast differentiation. This is particularly noteworthy as it has an opposite function to that in the TME of lung carcinoma, another PGE2 dependent tumor type. Here, sEV-derived miR-574-5p has an autokrine function that inhibits PGE2 biosynthesis in lung cancer cells. We report that the tetraspanin composition on the surface of sEV is associated with the function of sEV-derived miR-574-5p. This suggests that the vesicles do not only transport miRs, but also appear to influence their mode of action.Copyright © 2023 Proestler, Donzelli, Nevermann, Breitwieser, Koch, Best, Fauth, Wickström, Harter, Kogner, Lavieu, Larsson and Saul.