High impact of miRNA-4521 on FOXM1 expression in medulloblastoma.

Abstract

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although genetic variants are increasingly used in treatment stratification, survival of high-risk patients, characterized by leptomeningeal dissemination, TP53 mutation or MYC amplification, is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is deregulated in various solid tumors, including medulloblastoma, and triggers cellular proliferation, migration and genomic instability. In tissue samples obtained from medulloblastoma patients, the significant upregulation of FOXM1 was associated with a loss of its putative regulating microRNA, miR-4521. To understand the underlying mechanism, we investigated the effect of miR-4521 on the expression of the transcription factor FOXM1 in medulloblastoma cell lines. Transfection of this microRNA reduced proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through activation of caspase 3/7. Further, downstream targets of FOXM1 such as PLK1 and cyclin B1 were significantly reduced thus affecting the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may selectively suppress the pathophysiological effect of aberrant FOXM1 expression and serve as a targeted approach for medulloblastoma therapy.

• Authors: Daniel Senfter, Mahzeiar Samadaei, Robert M Mader, Johannes Gojo, Andreas Peyrl, Georg Krupitza, Marcel Kool, Martin Sill, Christine Haberler, Gerda Ricken, Thomas Czech, Irene Slavc, Sibylle Madlener
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 10 Pg. 696 (09 20 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31541075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• FOXM1 protein, human
• Forkhead Box Protein M1
• MIRN4521 microRNA, human
• MicroRNAs
• RNA, Messenger

Topics

• 3' Untranslated Regions
• Adolescent
• Brain Neoplasms (genetics, metabolism, pathology)
• Cell Cycle Checkpoints (physiology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Child
• Child, Preschool
• Down-Regulation
• Female
• Forkhead Box Protein M1 (biosynthesis, genetics, metabolism)
• Humans
• Infant
• Male
• Medulloblastoma (genetics, metabolism, pathology)
• MicroRNAs (biosynthesis, genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Spheroids, Cellular
• Up-Regulation