Document Detail


Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression.
MedLine Citation:
PMID:  24865424     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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; 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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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2014-05-27
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  124     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-07-03     Completed Date:  2014-10-06     Revised Date:  2014-10-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2861-76     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing*
Annexin A7 / genetics*
Brain Neoplasms / genetics*,  metabolism,  pathology
Cell Lineage / genetics
Cell Transformation, Neoplastic / genetics
Disease Progression
Exons
Gene Knockdown Techniques
Glioblastoma / genetics*,  metabolism,  pathology
Heterogeneous-Nuclear Ribonucleoproteins / antagonists & inhibitors,  genetics,  metabolism
Humans
MicroRNAs / genetics,  metabolism
Neoplastic Stem Cells / metabolism,  pathology
Neovascularization, Pathologic / genetics
Polypyrimidine Tract-Binding Protein / antagonists & inhibitors,  genetics,  metabolism
RNA, Messenger / genetics,  metabolism
RNA, Neoplasm / genetics,  metabolism
Receptor, Epidermal Growth Factor / genetics,  metabolism
Signal Transduction / genetics
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
P20 CA151129-01A1/CA/NCI NIH HHS; P30 CA016058/CA/NCI NIH HHS; T32 GM007250/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Annexin A7; 0/Heterogeneous-Nuclear Ribonucleoproteins; 0/MIRN124 microRNA, human; 0/MicroRNAs; 0/PTBP1 protein, human; 0/RNA, Messenger; 0/RNA, Neoplasm; 139076-35-0/Polypyrimidine Tract-Binding Protein; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor
Comments/Corrections

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