Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University, Halle (Saale), Germany.
Department of Pediatric Hematology/Oncology, University Hospital, Halle (Saale), Germany.
Pediatr Res. 2020 Mar;87(4):669-676. doi: 10.1038/s41390-019-0628-9. Epub 2019 Nov 22.
Glioblastoma (GBM) is the most aggressive form of glioma in adults and children and is associated with very poor prognosis. Pediatric tumors are biologically distinct from adult GBM and differ in response to current GBM treatment protocols. Regarding pediatric GBM, new drug combinations and the molecular background of chemotherapy effects need to be investigated, in order to increase patient survival outcome.
The expression of the RNA-binding protein Musashi1 (MSI1) in pediatric glioma samples of different WHO tumor grades was investigated on the protein (immunohistochemistry) and on the RNA level (publicly accessible RNA sequencing dataset). The impact of the chemotherapeutic temozolomide (TMZ) in combination with valproic acid (VPA) was tested in two pediatric glioblastoma-derived cell lines. The supportive effect of MSI1 expression against this treatment was investigated via transient knockdown and protein overexpression.
MSI1 expression correlates with pediatric high-grade glioma (HGG). The combination of TMZ with VPA significantly increases the impact of drug treatment on cell viability in vitro. MSI1 was found to promote drug resistance to the combined treatment with TMZ and VPA.
MSI1 expression is a potential marker for pediatric HGG and increases chemoresistance. Inhibition of MSI1 might lead to an improved patient outcome and therapy response.
胶质母细胞瘤（GBM）是成人和儿童中最具侵袭性的神经胶质瘤，预后极差。儿童肿瘤在生物学上与成人 GBM 不同，对目前的 GBM 治疗方案的反应也不同。关于儿童 GBM，需要研究新的药物组合和化疗效果的分子背景，以提高患者的生存结果。
研究了不同 WHO 肿瘤分级的小儿脑肿瘤样本中 RNA 结合蛋白 Musashi1（MSI1）的蛋白（免疫组织化学）和 RNA 水平（公开可用的 RNA 测序数据集）表达。在两种小儿脑胶质瘤衍生的细胞系中，测试了化疗药物替莫唑胺（TMZ）与丙戊酸（VPA）联合使用的效果。通过瞬时敲低和蛋白过表达研究了 MSI1 表达对这种治疗的支持作用。
MSI1 表达与小儿高级别胶质瘤（HGG）相关。TMZ 与 VPA 联合使用显著增加了药物治疗对体外细胞活力的影响。发现 MSI1 促进了对 TMZ 和 VPA 联合治疗的耐药性。
MSI1 表达是小儿 HGG 的一个潜在标志物，并增加了化疗耐药性。抑制 MSI1 可能会导致患者的预后和治疗反应得到改善。
