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Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression
Roberto Ferrarese, … , Maria S. Carro, Markus Bredel
Roberto Ferrarese, … , Maria S. Carro, Markus Bredel
Published May 27, 2014
Citation Information: J Clin Invest. 2014;124(7):2861-2876. https://doi.org/10.1172/JCI68836.
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Research Article Oncology Article has an altmetric score of 21

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

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Abstract

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.

Authors

Roberto Ferrarese, Griffith R. Harsh IV, Ajay K. Yadav, Eva Bug, Daniel Maticzka, Wilfried Reichardt, Stephen M. Dombrowski, Tyler E. Miller, Anie P. Masilamani, Fangping Dai, Hyunsoo Kim, Michael Hadler, Denise M. Scholtens, Irene L.Y. Yu, Jürgen Beck, Vinodh Srinivasasainagendra, Fabrizio Costa, Nicoleta Baxan, Dietmar Pfeifer, Dominik von Elverfeldt, Rolf Backofen, Astrid Weyerbrock, Christine W. Duarte, Xiaolin He, Marco Prinz, James P. Chandler, Hannes Vogel, Arnab Chakravarti, Jeremy N. Rich, Maria S. Carro, Markus Bredel

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Figure 6

Gene amplification and loss of a neuron-specific miRNA deregulate PTBP1 in glioblastomas.

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Gene amplification and loss of a neuron-specific miRNA deregulate PTBP1 ...
(A) PTBP1 gene copy numbers (amplification [Amp] vs. wild-type [WT] status) at the 19p13.3 locus across 537 glioblastomas and corresponding PTBP1 mRNA expression; overexpression and low expression denote higher-than-median and lower-than-median expression. (B) PTBP1 protein expression in a panel of patient-derived BTSCs (and normal brain) and corresponding copy number status of the PTBP1 gene showing high expression in both PTBP1-amplified and several nonamplified cells. (C) Linear regression of PTBP1 expression on PTBP1 gene dosage in 428 glioblastomas indicates a significant gene dosage effect on transcription (P = 7 × 10–8) and significantly higher expression of PTBP1 in PTBP1-amplified tumors compared with nonamplified tumors (P < 0.0000001 by Wilcoxon’s rank-sum test). P value in the linear regression model indicates statistical significance according to the estimated slope of the regression line. LOWESS smooth fit confirmed the appropriateness of a linear regression model. (D) qRT-PCR analysis of miR-124 and PTBP1 expression in normal human astrocytes, NPCs, A2B5-positive and -negative GPCs, patient-derived BTSCs, and glioblastoma tumor cell cultures, all normalized to expression in pooled normal brain. (E) Linear regression of PTBP1 mRNA expression on neuron-specific miR-124 expression in 428 glioblastomas indicated an inverse correlation (P = 0.000006). (F) Multiple regression model in 355 glioblastomas, confirming both PTBP1 gene dosage and miR-124 expression, is significantly associated with PTBP1 expression (P = 0.0001 and P = 0.00001, respectively; ordinary least-squares estimation). Graphical model validation by corresponding P-P plot indicates fit of probability distributions of observed versus estimated cumulative probabilities.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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