title: A large-scale analysis of alternative splicing reveals a key role of QKI in lung cancer.
abstract: Increasing interest has been devoted in recent years to the understanding of alternative splicing in cancer. In this study, we performed a genome-wide analysis to identify cancer-associated splice variants in non-small cell lung cancer. We discovered and validated novel differences in the splicing of genes known to be relevant to lung cancer biology, such as NFIB, ENAH or SPAG9. Gene enrichment analyses revealed an important contribution of alternative splicing to cancer-related molecular functions, especially those involved in cytoskeletal dynamics. Interestingly, a substantial fraction of the altered genes found in our analysis were targets of the protein quaking (QKI), pointing to this factor as one of the most relevant regulators of alternative splicing in non-small cell lung cancer. We also found that ESYT2, one of the QKI targets, is involved in cytoskeletal organization. ESYT2-short variant inhibition in lung cancer cells resulted in a cortical distribution of actin whereas inhibition of the long variant caused an increase of endocytosis, suggesting that the cancer-associated splicing pattern of ESYT2 has a profound impact in the biology of cancer cells. Finally, we show that low nuclear QKI expression in non-small cell lung cancer is an independent prognostic factor for disease-free survival (HR = 2.47; 95% CI = 1.11-5.46, P = 0.026). In conclusion, we identified several splicing variants with functional relevance in lung cancer largely regulated by the splicing factor QKI, a tumor suppressor associated with prognosis in lung cancer.
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: de Miguel
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez-Terroba
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ajona
authors.affiliation: Program in Immunology and Immunotherapy, CIMA, 31008 Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Morales
authors.affiliation: Group of Bioinformatics, CEIT and TECNUN, University of Navarra, 20018 San Sebastian, Spain.
authors.forename: Ravi D
authors.initials: RD
authors.lastname: Sharma
authors.affiliation: Department of Pathology, Clinica Universidad de Navarra, 31080 Pamplona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pardo
authors.affiliation: Department of Biochemistry and Genetics, School of Science, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain; Program in Immunology and Immunotherapy, CIMA, 31008 Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
authors.affiliation: Group of Bioinformatics, CEIT and TECNUN, University of Navarra, 20018 San Sebastian, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Rubio
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain. Electronic address: lmontuenga@unav.es.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: Program in Solid Tumors and Biomarkers, CIMA, 31008 Pamplona, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, 31008 Pamplona, Spain; Navarra's Health Research Institute (IDISNA), 31008 Pamplona, Spain. Electronic address: rpio@unav.es.
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D002966:Clathrin / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics*; D050857:Synaptotagmins / Q000378:metabolism
chemical_list: D002966:Clathrin; C490832:QKI protein, human; D016601:RNA-Binding Proteins; D050857:Synaptotagmins
keywords: Alternative splicing; ESYT2; Non-small cell lung cancer; QKI