Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas

Lhermitte, Benoît; Blandin, Anne-Florence; Coca, Andrés; Guérin, Éric; Durand, Aurélie; Entz‐Werlé, Natacha

doi:10.1016/j.neuchi.2018.01.003

Cited by 8 publications

(5 citation statements)

References 57 publications

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“…Another important tumor suppressor gene showing increased expression after Msi1 silencing is NDRG2, an n-MYC target gene, which is highly expressed in normal tissues, but undetectable in many tumors [ 51 ]. Groups 3 and 4 are characterized in part by NMYC and MYC-driven MBs [ 56 ]. Therefore, NDRG2 downregulation may be a crucial step in the context of these subgroups.…”

Section: Resultsmentioning

confidence: 99%

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The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

Baroni

Guardia

Lei

et al. 2021

Cells

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Medulloblastoma is the most common malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved survival in recent years, but patients are frequently left with devastating neurocognitive and other sequelae. Patients in molecular subgroups 3 and 4 still experience a high mortality rate. To identify new pathways contributing to medulloblastoma development and create new routes for therapy, we have been studying oncogenic RNA-binding proteins. We defined Musashi1 (Msi1) as one of the main drivers of medulloblastoma development. The high expression of Msi1 is prevalent in Group 4 and correlates with poor prognosis while its knockdown disrupted cancer-relevant phenotypes. Genomic analyses (RNA-seq and RIP-seq) indicated that cell cycle and division are the main biological categories regulated by Msi1 in Group 4 medulloblastoma. The most prominent Msi1 targets include CDK2, CDK6, CCND1, CDKN2A, and CCNA1. The inhibition of Msi1 with luteolin affected the growth of CHLA-01 and CHLA-01R Group 4 medulloblastoma cells and a synergistic effect was observed when luteolin and the mitosis inhibitor, vincristine, were combined. These findings indicate that a combined therapeutic strategy (Msi1 + cell cycle/division inhibitors) could work as an alternative to treat Group 4 medulloblastoma.

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Section: Resultsmentioning

confidence: 99%

“…Group 4 is the most common MB subgroup and its expression signature shows enrichment for neuronal development pathways [ 10 ], in which Msi1 is known to play fundamental roles [ 56 , 70 ]. The identification of oncogenic drivers of Group 4 MB has been challenging.…”

Section: Discussionmentioning

confidence: 99%

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

Baroni

Guardia

Lei

et al. 2021

Cells

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“…In contrast, oncogenes encode for protein factors that may be crucial for normal cell function [59]. Years after their original discovery, both groups are proven to be determinants of tumor classification, prognosis, response to cancer-related therapies, and indicators of clinical outcomes [60][61][62][63][64].…”

Section: An Overview Of the Genetics Of Cancer: Tumor Suppressor Gene...mentioning

confidence: 99%

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

Nejati-Koshki

Roberts

Babaei

et al. 2023

Cancers

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Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the “writers”, “readers”, and “erasers” of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.

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“…Medulloblastoma (MB) is the most common malignant neoplasm of the brain in childhood, constituting 15–30% of neurological tumors [ 1 , 2 ]. Advances in multi-modality therapies over the past 20 years have improved the overall 5-year survival rate of children with MB from 60 to 70% [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…New effective subgroup-specific therapies targeting distinct molecular markers are being developed to enhance the outlook for MB-affected children [ 13 ]. However, each MB subgroup presents unique heterogeneous transcription profiles, rendering treatments diverse and complicating drug development [ 1 ]. Thus, the identification of a common drug targeting homogeneously expressed biomarkers across the four MB subgroups holds pivotal significance in enhancing survival rates and mitigating postoperative toxicity for survivors [ 10 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

miR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression

Wang,

Fu,

Wang

et al. 2024

Cancer Gene Ther

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Medulloblastoma (MB), a prevalent pediatric central nervous system tumor, is influenced by microRNAs (miRNAs) that impact tumor initiation and progression. However, the specific involvement of miRNAs in MB tumorigenesis remains unclear. Using single-cell RNA sequencing, we identified ROR2 expression in normal human fetal cerebellum. Subsequent analyses, including immunofluorescence, quantitative real-time PCR (qRT-PCR), and Western blot, assessed ROR2 expression in MB tissues and cell lines. We investigated miR-124-3p and miR-194-5p and their regulatory role in ROR2 expression through the dual-luciferase reporter, qRT-PCR, and western blot assays. Mechanistic insights were gained through functional assays exploring the impact of miR-124-3p, miR-194-5p, and ROR2 on MB growth in vitro and in vivo. We observed significantly reduced miR-124-3p and miR-194-5p expression and elevated ROR2 expression in MB tissues and cell lines. High ROR2 expression inversely correlated with overall survival in WNT and SHH subgroups of MB patients. Functionally, overexpressing miR-124-3p and miR-194-5p and inhibiting ROR2 suppressed in vitro malignant transformation and in vivo tumorigenicity. Mechanistically, miR-124-3p and miR-194-5p synergistically regulated the ROR2/PI3K/Akt pathway, influencing MB progression. Our findings indicate that miR-124-3p and miR-194-5p function as tumor suppressors, inhibiting MB progression via the ROR2/PI3K/Akt axis, suggesting a key mechanism and therapeutic targets for MB patients.

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Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas

Cited by 8 publications

References 57 publications

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

The RNA-Binding Protein Musashi1 Regulates a Network of Cell Cycle Genes in Group 4 Medulloblastoma

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

miR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression

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