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Downregulation of 14q32 microRNAs in Primary Human Desmoplastic Medulloblastoma
Danielle Ribeiro Lucon1, Cristiane de Souza Rocha, Rogerio Bastos Craveiro
1Centro Infantil Boldrini , Campinas , Brazil ; Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas , Campinas , Brazil.
Abstract:
Medulloblastoma (MB) is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA) has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old). Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated) were found. Most downregulated miRNAs (32/64) were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor-γ (ESRRG), a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1), miR-206 (6p12.2), and miR-323-3p (14q32.2), were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. No effect was found with miR-206 or miR-323 mimics.
Insights
MicroRNA (miRNA) expression is altered in pediatric medulloblastoma (MB). The 14q32 miRNA locus is frequently downregulated, potentially due to epigenetic silencing, with miR-129-5p inhibiting cancer cell proliferation.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Genetics
Background:
- Medulloblastoma (MB) is a common pediatric brain tumor arising from aberrant cerebellar progenitor neuron development.
- MicroRNAs (miRNAs) are crucial regulators of central nervous system development and are implicated in various cancers.
- Understanding miRNA dysregulation in MB is vital for identifying novel therapeutic targets.
Purpose of the Study:
- To investigate miRNA expression profiles in young patients with desmoplastic medulloblastoma.
- To identify specific miRNA clusters and potential regulatory mechanisms involved in MB pathogenesis.
- To evaluate the functional impact of selected miRNAs on medulloblastoma cell proliferation.
Main Methods:
- Microarray analysis of miRNA expression in desmoplastic MB versus normal cerebellum.
- Bioinformatic analysis of publicly available gene expression datasets to explore regulatory mechanisms.
- Functional studies using miRNA mimics in DAOY medulloblastoma cell lines.
Main Results:
- Identified 84 differentially expressed miRNAs, with 64 downregulated and 20 upregulated.
- Observed significant downregulation of miRNAs from the 14q32 locus, suggesting coordinated regulation.
- Found reduced expression of ESRRG and MEG3 in MB, indicating potential transcriptional and epigenetic silencing of the 14q32 locus.
- Demonstrated that miR-129-5p overexpression inhibits proliferation in DAOY cells, while miR-206 and miR-323-3p had no significant effect.
Conclusions:
- The 14q32 miRNA locus is a frequently dysregulated module in pediatric desmoplastic MB.
- Epigenetic silencing and altered transcriptional regulation may contribute to 14q32 miRNA downregulation.
- miR-129-5p exhibits tumor-suppressive activity in medulloblastoma, highlighting its potential as a therapeutic target.
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