Tissue-Regulated Splicing Promotes EGFR Signaling in Glioblastoma

Regulation of mRNA splicing is critical for normal developmental processes such as neuronal differentiation in the brain, and aberrant alternative splicing can generate variant protein isoforms that promote oncogenic transformation and glioblastoma progression. However, the role of tissue-specific splicing of alternative exons in tumorigenesis remains unclear. Ferrarese and colleagues hypothesized that alternative splicing of annexin A7 (ANXA7), a membrane-bound tumor suppressor that undergoes tissue-specific exon skipping in the brain, contributes to glioblastoma progression. In support of this idea, expression of ANXA7 isoform 2, which lacks the alternative exon, was elevated in glioblastoma tissue as well as in neural and glial progenitor cells, which represent potential glioblastoma cells of origin. In contrast to the full-length ANXA7 isoform 1, ANXA7 isoform 2 lacked the ability to terminate EGFR signaling via endosomal targeting and degradation, suggesting that alternative splicing of ANXA7 enhances oncogenic EGFR activity. Exon skipping in ANXA7 was mediated by polypyrimidine tract-binding protein 1 (PTBP1), a heterogeneous nuclear ribonucleoprotein that was upregulated in glioblastomas compared with normal brain tissue via gene amplification and loss of the neuron-specific miRNA miR-124. Depletion of PTBP1 in glioblastoma or brain tumor stem cells increased ANXA7 isoform 1 expression, diminished EGFR activation, and inhibited glioblastoma invasion and angiogenesis; these phenotypes were rescued by concomitant silencing of ANXA7 isoform 1, suggesting that PTBP1-driven splicing promotes brain tumor progression by disrupting the tumor-suppressive function of ANXA7 in endocytosis. In addition, high PTBP1 expression was associated with shorter survival in patients with glioblastoma, similar to patients with EGFR amplification, further underscoring the importance of PTBP1-dependent activation of EGFR in glioblastoma progression. These results provide insight into how posttranscriptional, lineage-specific splicing of a tumor suppressor can reprogram normal developmental processes to stimulate oncogenic signaling and tumorigenesis.

Ferrarese R, Harsh GR, IV, Yadav AK, Bug E, Maticzka D, Reichardt W, et al. Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression. J Clin Invest 2014;124:2861–76.

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