Impact of miRNA-mRNA Profiling and Their Correlation on Medulloblastoma Tumorigenesis

Vinod Kumar,Virender Kumar,Amit Kumar Chaudhary,Donald W Coulter,Timothy Mcguire,Ram I Mahato

doi:10.1016/j.omtn.2018.06.004

Vinod Kumar, Virender Kumar + Show 4 more

Open Access

https://doi.org/10.1016/j.omtn.2018.06.004

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Abstract

Medulloblastoma (MB) is a clinically challenging, childhood brain tumor with a diverse genetic makeup and differential miRNA profile. Aiming to identify deregulated miRNAs in MB, the miRNA expression profile of human MB samples was compared to that of normal cerebellar tissues. As a result, 8 upregulated and 64 downregulated miRNAs were identified in MB samples. Although various algorithms have been developed to predict the interaction between miRNA-mRNA pairs, the complexity and fidelity of miRNA-mRNA remain a concern. Therefore, to identify the signatures of miRNA-mRNA interactions essential for MB pathogenesis, miRNA profiling, RNA sequencing, and ingenuity pathway analysis (IPA) were performed in the same primary human MB samples. Further, when miR-217 was inhibited, a significant upregulation of predicted target genes SIRT1, ROBO1, FOXO3, and SMAD7 in HDMB03 cells was observed, confirming the validity of our approach. Functional analysis revealed that the inhibition of miR-217 in HDMB03 cells suppresses colony formation, migration, invasion, promoted apoptosis, and arrested cell population in S phase, indicating that manipulation of miR-217 may have a therapeutic potential for MB patients. Therefore, our study provides an essential platform for future investigations of specific miRNAs responsible for MB pathogenesis.

Highlights

Medulloblastoma (MB) is the most common malignant brain tumor in children, mainly arising in the cerebellum.[1,2] MB is classified into four subgroups: wingless (Wnt) group, sonic hedgehog (Shh) group, group 3, and group 4.3–5 Each subgroup has different origins and pathogenesis and differs in genetic signature and in response to clinical therapy
We identified several differentially expressed genes, miRNAs, miRNA-mRNA correlations, and canonical pathways that may lead to actionable targets in MB
Despite tremendous clinical and biological heterogeneity, treatment of MB is relatively uniform and consists of surgery followed by craniospinal radiation and chemotherapy.[1]

Summary

Introduction

Medulloblastoma (MB) is the most common malignant brain tumor in children, mainly arising in the cerebellum.[1,2] MB is classified into four subgroups: wingless (Wnt) group, sonic hedgehog (Shh) group, group 3, and group 4.3–5 Each subgroup has different origins and pathogenesis and differs in genetic signature and in response to clinical therapy. Beside these classifications, Schwalbe et al.[6] further classified MB into seven subgroups, and Cavalli et al.[7] further classified MB into 12 subgroups. It is important to understand the genetic, epigenetic, and translational programs that drive MB tumorigenesis and can lead to the development of novel therapeutics

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