Knockdown of Musashi-1 enhances chemotherapeutic sensitivity and apoptosis in Group 3/4 medulloblastomas cells

Abstract: Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. The RNA-binding protein Musashi-1 (MSI1) is a neural stem cell marker, characterized as a gene translation regulator and associated with high oncogenicity in several human cancers. In this study, we investigated the clinical significance and biological functions of MSI1 in Grp3/Grp4-MBs. First, we assessed the expression profile of MSI1 in 59 primary MB samples (15-WNT, 18-SHH, 9-Grp3, 17-Grp4 subgroups) by qRT-PCR. MSI1 mRNA expression levels were also validated in an additional public dataset of MBs (GSE85217). The ROC curve was used to validate the diagnostic standards of MSI1 expression. Cell cycle, cell viability, and apoptosis were evaluated in D283 Med cell-line (Grp3/Grp4/MBs) after shRNA-mediated knockdown of MSI1 plus cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non- Grp3/Grp4-MBs. In addition, MSI1 knockdown promoted cell cycle interruption in the G1/S transition and, consequently, decreased the number of cells in the G2/M phase, repressed cell proliferation and sensitized D283 Med cells to cisplatin treatment by enhancing cell apoptosis. The results of the present study are the first to demonstrate that MSI1 may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.