Transcriptional Differences between Normal and Glioma-Derived Glial Progenitor Cells Identify a Core Set of Dysregulated Genes

Auvergne, Romane; Sim, Fraser J.; Wang, Su; Chandler-Militello, Devin; Burch, Jaclyn E; Al Fanek, Yazan; Davis, Danielle R.; Benraiss, Abdellatif; Walter, K.C.; Achanta, Pragathi; Johnson, Mahlon D.; Quiñones‐Hinojosa, Alfredo; Natesan, Sridaran; Ford, Heide L.; Goldman, Steven A.

doi:10.1016/j.celrep.2013.06.033

Cited by 7 publications

(8 citation statements)

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“…In the brain, PTBP1 expression is restricted to non-neuronal lineages such as astrocytes and neural progenitors (45), which we further confirmed for A2B5-positive and A2B5-negative glial progenitor cells (87,88). We found that PTBP1 was highly expressed in glioblastomas through downregulation of miRNA-124.…”

Section: Methodssupporting

confidence: 56%

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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Section: Methodssupporting

confidence: 56%

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

et al. 2014

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“…In addition, Six1 plays a role in cellular migration and invasion during embryogenesis (22,(27)(28)(29)(30) and in breast cancer (31,32). Notably, a recent study demonstrated that messenger RNA profiling of Six1 is dysregulated in A2B5 + glioma tumor progenitor cells from A2B5 + glial progenitor cells isolated from normal white matter (33).…”

Section: Six1 Expression N -----------------------------------------mentioning

confidence: 99%

Six1 expression is associated with a poor prognosis in patients with glioma

Zhang

2017

Oncology Letters

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Abstract. Glioma is the most common human brain cancer and has poor prognosis. Messenger RNA profiling identified that sineoculis homeobox homolog 1 (Six1) is dysregulated in glioma tumor progenitor cells from glial progenitor cells isolated from normal white matter. However, the expression and role of Six1 in glioma remains unclear. The purpose of the present study was to investigate the expression level of Six1 in glioma tissues and the association between Six1 expression and clinicopathological characteristics and prognosis of gliomas. The Six1 protein was detected by immunohistochemistry in 163 glioma tissues of distinct malignancy grades, and Kaplan-Meier survival analysis was performed to assess the prognosis of the patients. The Six1 protein was stained in 49.1% (80 out of 163) of the glioma tissues, including 34.2% of low-grade [World Health Organization (WHO) I/II] gliomas and 80.8% of high-grade (WHO III/IV) gliomas. Normal brain tissues rarely expressed the Six1 protein. In addition, Six1 expression was significantly associated with WHO grade (P<0.001). According to the log-rank test and Cox regression model, Six1 may be suggested as an independent prognostic factor, in addition to the WHO grade. Overall, Six1 protein expression varies between different grades of glioma and is associated with the WHO grade. Upregulation of Six1 is more frequent in high-grade glioma and is an independent prognostic factor of poor clinical outcome.

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“…These data suggest that Six1 and Eya cooperate in normal development of human and mouse tissues. Importantly, the Six1-Eya complex is overexpressed in many different tumor types, including Wilms' tumor, ovarian cancer, acute leukemia, malignant peripheral nerve-sheath tumors, glioblastomas, and breast cancer (8,(15)(16)(17)(18)(19)(20). We have recently demonstrated that Eya2 knockdown inhibits the ability of Six1 to induce TGF-␤ signaling, epithelial-to-mesenchymal transition, and tumor-initiating cell characteristics in breast cancer, properties that are associated with Six1-induced breast tumorigenesis and metastasis (17).…”

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confidence: 99%

Allosteric Inhibitors of the Eya2 Phosphatase Are Selective and Inhibit Eya2-mediated Cell Migration

Krueger

Drasin

Lea

et al. 2014

Journal of Biological Chemistry

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Background:The phosphatase activity of Eya is important for transformation, invasion, migration, and metastasis of breast cancer cells. Results: A class of N-arylidenebenzohydrazide compounds specifically inhibits the phosphatase activity of Eya2 but not Eya3. Conclusion: This class of compounds likely acts through an allosteric mechanism. Significance: These inhibitors may be developed into chemical probes or anti-cancer drugs.

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Transcriptional Differences between Normal and Glioma-Derived Glial Progenitor Cells Identify a Core Set of Dysregulated Genes

Cited by 7 publications

References 0 publications

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

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

Six1 expression is associated with a poor prognosis in patients with glioma

Allosteric Inhibitors of the Eya2 Phosphatase Are Selective and Inhibit Eya2-mediated Cell Migration

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