miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion

Fowler, Adam; Thomson, Daniel; Giles, Keith M.; Maleki, Saeed; Mreich, Ellein; Wheeler, Helen; Leedman, Peter J.; Biggs, Michael T.; Cook, Raymond; Little, Nicholas; Robinson, B. W.; McDonald, Kerrie L.

doi:10.1016/j.ejca.2010.11.026

Cited by 119 publications

(102 citation statements)

References 39 publications

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“…2,22 Conversely, many of the miRNAs downregulated in astrocytomas relative to oligodendrogliomas have been shown to be required in maintaining astrocytic differentiation, including miR-124 4 and miR-128.…”

Section: Diagnostic Uncertainty In Discriminating Betweenmentioning

confidence: 99%

The Cancer Genome Atlas expression profiles of low-grade gliomas

Gonda

Cheung

Muller

et al. 2014

FOC

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Differentiating between low-grade gliomas (LGGs) of astrocytic and oligodendroglial origin remains a major challenge in neurooncology. Here the authors analyzed The Cancer Genome Atlas (TCGA) profiles of LGGs with the goal of identifying distinct molecular characteristics that would afford accurate and reliable discrimination of astrocytic and oligodendroglial tumors. They found that 1) oligodendrogliomas are more likely to exhibit the glioma-CpG island methylator phenotype (G-CIMP), relative to low-grade astrocytomas; 2) relative to oligodendrogliomas, low-grade astrocytomas exhibit a higher expression of genes related to mitosis, replication, and inflammation; and 3) low-grade astrocytic tumors harbor microRNA profiles similar to those previously described for glioblastoma tumors. Orthogonal intersection of these molecular characteristics with existing molecular markers, such as IDH1 mutation, TP53 mutation, and 1p19q status, should facilitate accurate and reliable pathological diagnosis of LGGs.

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Section: Diagnostic Uncertainty In Discriminating Betweenmentioning

confidence: 99%

The Cancer Genome Atlas expression profiles of low-grade gliomas

Gonda

Cheung

Muller

et al. 2014

FOC

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“…However, many tumors had overexpression of the PTBP1 transcript ( Figure 6A) and protein ( Figure 6B) without gene amplification. Neuron-specific microRNA miR-124, which plays an important role in neurogenesis (80) and is repressed in high-grade gliomas (81)(82)(83) to enhance stem-like traits and invasiveness (84), directly targets PTBP1 during nervous system development (44). Our analysis of miR-124 expression in a panel of patient-derived BTSCs revealed consistently lower levels of miR-124 in glioblastoma-derived BTSCs and tumor cell cultures than were seen in normal brain and, in turn, showed higher levels of PTBP1 expression in the BTSCs and tumor cultures ( Figure 6D).…”

Section: Figurementioning

confidence: 99%

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

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Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

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“…miR-7 directly regulates the expression of EGFR in glioblastoma and has also been shown to directly attenuate the activation of AKT and ERK1/2 (extracellular signal-regulated kinase) indicating its ability to co-ordinately regulate EGFR signalling (Webster et al 2009). We also showed that miR-124a attenuated glioblastoma migration and invasion at multiple points of the pathway (Fowler et al 2011). New technologies are currently being developed to facilitate the use of miRNAs as a realistic therapeutic option.…”

Section: A Pathway-centric Approach Is Neededmentioning

confidence: 99%

Biomarker Discovery, Validation and Clinical Application for Patients Diagnosed with Glioma

McDonald¹

2011

Glioma - Exploring Its Biology and Practical Relevance

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miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion

Cited by 119 publications

References 39 publications

The Cancer Genome Atlas expression profiles of low-grade gliomas

The Cancer Genome Atlas expression profiles of low-grade gliomas

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Biomarker Discovery, Validation and Clinical Application for Patients Diagnosed with Glioma

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