Musashi-1 regulates cell cycle and confers resistance to cisplatin treatment in Group 3/4 medulloblastomas cells

Author:

Chagas Pablo Shimaoka1ORCID,Veronez Luciana Chain2,de Sousa Graziella Ribeiro2,Cruzeiro Gustavo Alencastro Veiga3,Corrêa Carolina Alves Pereira2,Saggioro Fabiano Pinto2,Queiroz Rosane Gomes de Paula2,Marie Suely Kazue Nagahashi2,Brandalise Silvia Regina4,Cardinalli Izilda Aparecida5,Yunes José Andres5,Júnior Carlos Gilberto Carlotti2,Machado Hélio Rubens2,Santos Marcelo Volpon2,Scrideli Carlos Alberto2,Tone Luiz Gonzaga2,Valera Elvis Terci2

Affiliation:

1. Universidade de São Paulo Faculdade de Ciências Farmacêuticas de Ribeirão Preto

2. University of Sao Paulo: Universidade de Sao Paulo

3. Harvard Medical School

4. Boldrini Children Center

5. Boldrini

Abstract

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. In this study, we investigated the clinical significance and biological functions of Musashi-1 (MSI1) in Grp3 and 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. Next, the potential correlated cell-cycle genes were measured by RNA-Seq. Cell cycle, cell viability, and apoptosis were evaluated in a Grp3/Grp4 MB cell line after knockdown of MSI1 and cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non-Grp3/Grp4-MBs. We identified that MSI1 knockdown not only triggered transcriptional changes in the cell cycle pathway, but also affected G2/M phase in vitro, supporting the role of knockdown of MSI1 in cell cycle arrest. Lastly, MSI1 knockdown decreased cell viability and sensitized D283-Med cells to cisplatin treatment by enhancing cell apoptosis. Based on these findings, we suggest that MSI1 modulates cell cycle progression and 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.

Publisher

Research Square Platform LLC

Reference39 articles.

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5. Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, Rutkowski S, Ellison DW, Malkin D, Taylor MD et al. Medulloblastoma. Nat Rev Dis Primers 2019, 5(1):11.

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