MSI1 promotes the expression of the GBM stem cell marker CD44 by impairing miRNA-dependent degradation. [miRNA-Seq]

The stem cell marker Musashi1 (MSI1) is highly expressed during neurogenesis and in Glioblastoma (GBM). In cancer and non-malignant progenitor cells, MSI1 promotes self-renewal and impairs differentiation, involving the regulation of mRNA translation. However, a comprehensive understanding of MSI1's role in promoting GBM-driving networks remains to be deciphered. Overall design: In this study we use GBM-derived in vitro models of pediatric and adult origin, including isolated primary tumorspheres, to characterize GBM-driving roles of MSI1. We demonstrate that MSI1 is highly expressed in GBM recurrences, a major defiance in terms of surgery and chemo-/radiotherapy. In adult as well as pediatric GBM cell models, MSI1 promotes stem cell-like characteristics, most prominently elevated self-renewal potential and de-differentiation. For the first time, we provide evidence that MSI1 promotes the expression of stem cell markers like CD44, co-expressed with MSI1 within the migrating cell front of primary GBM samples. In GBM cell models MSI1 impairs CD44 downregulation by miRNAs revealing a new function of MSI1 in promoting stem cell properties, the 3'UTR- and miRNA-dependent control of mRNA turnover. This regulation is impaired by the previously reported MSI1 inhibitor luteolin. In sum, our findings reveal a role of MSI1 in stabilizing stem cell marker-encoding mRNAs in GBM and provide further evidence for its therapeutic target potential in GBM treatment.

干细胞标志物Musashi1（MSI1）在神经发生过程及胶质母细胞瘤（Glioblastoma，GBM）中呈高表达。在肿瘤细胞与非恶性祖细胞中，MSI1可促进自我更新并抑制分化，其作用机制涉及mRNA翻译调控。然而，学界对MSI1介导胶质母细胞瘤驱动网络的具体功能仍有待全面阐明。

本研究整体设计：本研究采用源自儿童与成人胶质母细胞瘤的体外模型，包括分离获得的原代肿瘤球，以解析MSI1在胶质母细胞瘤驱动过程中的作用。研究证实，MSI1在胶质母细胞瘤复发灶中呈高表达，而复发灶是手术及放化疗面临的主要治疗挑战。在成人及儿童胶质母细胞瘤细胞模型中，MSI1可诱导干细胞样特性，最显著的表现为自我更新能力增强及去分化现象。本研究首次证明，MSI1可促进CD44等干细胞标志物的表达，且CD44与MSI1共定位于原发性胶质母细胞瘤样本的迁移细胞前沿区域。在胶质母细胞瘤细胞模型中，MSI1可阻断微小RNA（miRNA）对CD44的下调作用，由此揭示了MSI1调控干细胞特性的全新功能：即依赖3'非翻译区（3'UTR）与微小RNA的mRNA周转调控。此前报道的MSI1抑制剂木犀草素可阻断该调控通路。

综上，本研究揭示了MSI1在胶质母细胞瘤中稳定编码干细胞标志物的mRNA的功能，并为其作为胶质母细胞瘤治疗的潜在治疗靶点提供了新的实验依据。