{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T03:04:10Z","timestamp":1768791850118,"version":"3.49.0"},"reference-count":203,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BIA-MOL\/28386\/2017"],"award-info":[{"award-number":["PTDC\/BIA-MOL\/28386\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/MULTI\/04046\/2019"],"award-info":[{"award-number":["UID\/MULTI\/04046\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Maratona da sa\u00fade","award":["Cancro 2014"],"award-info":[{"award-number":["Cancro 2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity. In the past decade, genome-wide transcriptome sequencing has revealed that AS is tightly regulated in a tissue- and developmental stage-specific manner, and also frequently dysregulated in multiple human cancer types. It is currently recognized that splicing defects, including genetic alterations in the spliced gene, altered expression of both core components or regulators of the precursor messenger RNA (pre-mRNA) splicing machinery, or both, are major drivers of tumorigenesis. Hence, in this review we provide an overview of our current understanding of splicing alterations in cancer, and emphasize the need to further explore the cancer-specific splicing programs in order to obtain new insights in oncology. Furthermore, we also discuss the recent advances in the identification of dysregulated splicing signatures on a genome-wide scale and their potential use as biomarkers. Finally, we highlight the therapeutic opportunities arising from dysregulated splicing and summarize the current approaches to therapeutically target AS in cancer.<\/jats:p>","DOI":"10.3390\/ijms21239032","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T03:51:16Z","timestamp":1606535476000},"page":"9032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Alternative Splicing: Expanding the Landscape of Cancer Biomarkers and Therapeutics"],"prefix":"10.3390","volume":"21","author":[{"given":"Cl\u00e1udia","family":"Bessa","sequence":"first","affiliation":[{"name":"Department of Human Genetics, National Health Institute Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-9696","authenticated-orcid":false,"given":"Paulo","family":"Matos","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Health Institute Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1425-9211","authenticated-orcid":false,"given":"Peter","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Health Institute Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1934-4279","authenticated-orcid":false,"given":"V\u00e2nia","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Health Institute Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.tibs.2017.04.001","article-title":"The Relationship between Alternative Splicing and Proteomic Complexity","volume":"42","author":"Blencowe","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/nature07509","article-title":"Alternative isoform regulation in human tissue transcriptomes","volume":"456","author":"Wang","year":"2008","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s00424-018-2136-x","article-title":"Alternative splicing isoforms in health and disease","volume":"470","author":"Kim","year":"2018","journal-title":"Pflug. Arch."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/ng.259","article-title":"Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing","volume":"40","author":"Pan","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7647","DOI":"10.1158\/0008-5472.CAN-04-1910","article-title":"Aberrant and alternative splicing in cancer","volume":"64","author":"Venables","year":"2004","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.cell.2014.01.051","article-title":"Synonymous mutations frequently act as driver mutations in human cancers","volume":"156","author":"Supek","year":"2014","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1038\/ng.3414","article-title":"Intron retention is a widespread mechanism of tumor-suppressor inactivation","volume":"47","author":"Jung","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4422","DOI":"10.1093\/hmg\/ddr370","article-title":"Increased levels of noisy splicing in cancers, but not for oncogene-derived transcripts","volume":"20","author":"Chen","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13073-015-0168-9","article-title":"Widespread intron retention diversifies most cancer transcriptomes","volume":"7","author":"Dvinge","year":"2015","journal-title":"Genome Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nrc.2016.51","article-title":"RNA splicing factors as oncoproteins and tumour suppressors","volume":"16","author":"Dvinge","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/cdd.2016.91","article-title":"Alternative splicing and cell survival: From tissue homeostasis to disease","volume":"23","author":"Paronetto","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1101\/gr.473902","article-title":"Large-scale proteomic analysis of the human spliceosome","volume":"12","author":"Rappsilber","year":"2002","journal-title":"Genome Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S1097-2765(03)00270-3","article-title":"Pre-mRNA splicing: Awash in a sea of proteins","volume":"12","author":"Jurica","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e1527","DOI":"10.1002\/wrna.1527","article-title":"Splicing and cancer: Challenges and opportunities","volume":"10","author":"Coltri","year":"2019","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.celrep.2017.07.025","article-title":"Impact of Alternative Splicing on the Human Proteome","volume":"20","author":"Liu","year":"2017","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrg2776","article-title":"Alternative splicing and evolution: Diversification, exon definition and function","volume":"11","author":"Keren","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1261\/rna.876308","article-title":"Splicing regulation: From a parts list of regulatory elements to an integrated splicing code","volume":"14","author":"Wang","year":"2008","journal-title":"RNA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev-biochem-060614-034316","article-title":"Mechanisms and Regulation of Alternative Pre-mRNA Splicing","volume":"84","author":"Lee","year":"2015","journal-title":"Annu Rev. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ccell.2018.07.001","article-title":"Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients","volume":"34","author":"Kahles","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.molcel.2013.11.010","article-title":"RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation","volume":"52","author":"Bechara","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.celrep.2015.09.053","article-title":"Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3\u2032 Splice Site Selection through Use of a Different Branch Point","volume":"13","author":"Darman","year":"2015","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6042","DOI":"10.1038\/ncomms7042","article-title":"Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome","volume":"6","author":"Madan","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zong, F.Y., Fu, X., Wei, W.J., Luo, Y.G., Heiner, M., Cao, L.J., Fang, Z., Fang, R., Lu, D., and Ji, H. (2014). The RNA-binding protein QKI suppresses cancer-associated aberrant splicing. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004289"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.celrep.2018.03.052","article-title":"Systematic Analysis of Splice-Site-Creating Mutations in Cancer","volume":"23","author":"Jayasinghe","year":"2018","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nature10496","article-title":"Frequent pathway mutations of splicing machinery in myelodysplasia","volume":"478","author":"Yoshida","year":"2011","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1200\/JCO.2011.40.7379","article-title":"Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes","volume":"30","author":"Bejar","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3616","DOI":"10.1182\/blood-2013-08-518886","article-title":"Chronic Myeloid Disorders Working Group of the International Cancer Genome, C., Clinical and biological implications of driver mutations in myelodysplastic syndromes","volume":"122","author":"Papaemmanuil","year":"2013","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41571-020-0350-x","article-title":"Roles and mechanisms of alternative splicing in cancer\u2014implications for care","volume":"17","author":"Bonnal","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"DeBoever, C., Ghia, E.M., Shepard, P.J., Rassenti, L., Barrett, C.L., Jepsen, K., Jamieson, C.H., Carson, D., Kipps, T.J., and Frazer, K.A. (2015). Transcriptome sequencing reveals potential mechanism of cryptic 3\u2032 splice site selection in SF3B1-mutated cancers. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004105"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10615","DOI":"10.1038\/ncomms10615","article-title":"Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage","volume":"7","author":"Alsafadi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/emboj.2011.367","article-title":"A syn-anti conformational difference allows SRSF2 to recognize guanines and cytosines equally well","volume":"31","author":"Daubner","year":"2012","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ccell.2015.04.006","article-title":"SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition","volume":"27","author":"Kim","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_34","first-page":"4726","article-title":"Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities","volume":"112","author":"Zhang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.celrep.2018.01.088","article-title":"Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types","volume":"23","author":"Seiler","year":"2018","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1101\/gr.181016.114","article-title":"U2AF1 mutations alter splice site recognition in hematological malignancies","volume":"25","author":"Ilagan","year":"2015","journal-title":"Genome Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Fei, D.L., Motowski, H., Chatrikhi, R., Prasad, S., Yu, J., Gao, S., Kielkopf, C.L., Bradley, R.K., and Varmus, H. (2016). Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival. PLoS Genet., 12.","DOI":"10.1101\/048553"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1158\/2159-8290.CD-13-0253","article-title":"Misregulation of pre-mRNA alternative splicing in cancer","volume":"3","author":"Zhang","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2174\/138920208786847971","article-title":"Alternative splicing and tumor progression","volume":"9","author":"Ghigna","year":"2008","journal-title":"Curr. Genom."},{"key":"ref_41","first-page":"5818","article-title":"Altered expression of heterogenous nuclear ribonucleoproteins and SR factors in human colon adenocarcinomas","volume":"58","author":"Ghigna","year":"1998","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/embor.2008.189","article-title":"The emerging role of splicing factors in cancer","volume":"9","author":"Grosso","year":"2008","journal-title":"EMBO Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/onc.2015.318","article-title":"Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes","volume":"35","author":"Sveen","year":"2016","journal-title":"Oncogene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nsmb1209","article-title":"The gene encoding the splicing factor SF2\/ASF is a proto-oncogene","volume":"14","author":"Karni","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nsmb.2207","article-title":"The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation","volume":"19","author":"Anczukow","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.molcel.2015.09.005","article-title":"SRSF1-Regulated Alternative Splicing in Breast Cancer","volume":"60","author":"Anczukow","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.molcel.2005.10.026","article-title":"Cell motility is controlled by SF2\/ASF through alternative splicing of the Ron protooncogene","volume":"20","author":"Ghigna","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.canlet.2017.03.013","article-title":"Splicing factors of SR and hnRNP families as regulators of apoptosis in cancer","volume":"396","author":"Kedzierska","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_49","first-page":"4048","article-title":"Heterogeneous nuclear ribonucleoprotein A2\/B1 up-regulation in bronchial lavage specimens: A clinical marker of early lung cancer detection","volume":"5","author":"Fielding","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0169-5002(01)00254-9","article-title":"Expression of early lung cancer detection marker: hnRNP-A2\/B1 and its relation to microsatellite alteration in non-small cell lung cancer","volume":"34","author":"Zhou","year":"2001","journal-title":"Lung Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1023\/A:1010631915831","article-title":"Differential expression of the early lung cancer detection marker, heterogeneous nuclear ribonucleoprotein-A2\/B1 (hnRNP-A2\/B1) in normal breast and neoplastic breast cancer","volume":"66","author":"Zhou","year":"2001","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4464","DOI":"10.1158\/0008-5472.CAN-10-4410","article-title":"Splicing factor hnRNP A2\/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma","volume":"71","author":"Cohen","year":"2011","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Goncalves, V., Pereira, J.F.S., and Jordan, P. (2017). Signaling Pathways Driving Aberrant Splicing in Cancer Cells. Genes, 9.","DOI":"10.3390\/genes9010009"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1101\/gr.193169.115","article-title":"A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway emanating from ELK1","volume":"26","author":"Hollander","year":"2016","journal-title":"Genome Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1083\/jcb.201001073","article-title":"Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2\/ASF proto-oncogene","volume":"191","author":"Valacca","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nature01153","article-title":"Signal-dependent regulation of splicing via phosphorylation of Sam68","volume":"420","author":"Matter","year":"2002","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1083\/jcb.149.2.307","article-title":"The MKK(3\/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation","volume":"149","author":"Lozano","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1073\/pnas.0409889102","article-title":"Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock","volume":"102","author":"Allemand","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9185","DOI":"10.1158\/0008-5472.CAN-10-1545","article-title":"Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase\/Akt pathway via phosphorylation of SRp30a","volume":"70","author":"Shultz","year":"2010","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1172\/JCI43552","article-title":"hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing","volume":"120","author":"Goehe","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"8575","DOI":"10.1074\/jbc.M112.443333","article-title":"hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L","volume":"288","author":"Vu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/nsmb1020","article-title":"Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT","volume":"12","author":"Blaustein","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1093\/hmg\/ddp317","article-title":"Antagonistic SR proteins regulate alternative splicing of tumor-related Rac1b downstream of the PI3-kinase and Wnt pathways","volume":"18","author":"Goncalves","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1261\/rna.041376.113","article-title":"Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells","volume":"20","author":"Goncalves","year":"2014","journal-title":"RNA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1261\/rna.1253408","article-title":"The beta-catenin\/TCF4 pathway modifies alternative splicing through modulation of SRp20 expression","volume":"14","author":"Goncalves","year":"2008","journal-title":"RNA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3389\/fmolb.2018.00080","article-title":"The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer","volume":"5","author":"Younis","year":"2018","journal-title":"Front. Mol. Biosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3109\/10428199809058352","article-title":"BCL-X and the apoptotic machinery of lymphoma cells","volume":"28","author":"Xerri","year":"1998","journal-title":"Leuk. Lymphoma"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3892\/or.2015.4465","article-title":"Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines","volume":"35","author":"Li","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_69","first-page":"230","article-title":"Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases","volume":"3","author":"Olopade","year":"1997","journal-title":"Cancer J. Sci. Am."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"49374","DOI":"10.1074\/jbc.M209236200","article-title":"Cellular response to an antisense-mediated shift of Bcl-x pre-mRNA splicing and antineoplastic agents","volume":"277","author":"Mercatante","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1053\/jhep.2001.25387","article-title":"Expression and role of Bcl-xL in human hepatocellular carcinomas","volume":"34","author":"Takehara","year":"2001","journal-title":"Hepatology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/path.4129","article-title":"The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers","volume":"229","author":"Siegfried","year":"2013","journal-title":"J. Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.celrep.2014.03.041","article-title":"Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation","volume":"7","author":"Maimon","year":"2014","journal-title":"Cell Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Chao, T.K., Huang, T.S., Liao, Y.P., Huang, R.L., Su, P.H., Shen, H.Y., Lai, H.C., and Wang, Y.C. (2017). Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182166"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/cas.13211","article-title":"Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism","volume":"108","author":"Shiroki","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"846","DOI":"10.18632\/oncotarget.2749","article-title":"PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1158\/1535-7163.MCT-14-0142","article-title":"Significance of Polypyrimidine Tract-Binding Protein 1 Expression in Colorectal Cancer","volume":"14","author":"Takahashi","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/sj.onc.1206075","article-title":"Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: Generation of different splicing RON variants and their oncogenic potential","volume":"22","author":"Zhou","year":"2003","journal-title":"Oncogene"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3892\/or.2015.3995","article-title":"RON alternative splicing regulation in primary ovarian cancer","volume":"34","author":"Mayer","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1111\/j.1471-4159.2009.06027.x","article-title":"RON receptor tyrosine kinase in human gliomas: Expression, function, and identification of a novel soluble splice variant","volume":"109","author":"Eckerich","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Krishnaswamy, S., Mohammed, A.K., Tripathi, G., Alokail, M.S., and Al-Daghri, N.M. (2017). Splice variants of the extracellular region of RON receptor tyrosine kinase in lung cancer cell lines identified by PCR and sequencing. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3747-x"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1128\/MCB.16.10.5518","article-title":"A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype","volume":"16","author":"Collesi","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.celrep.2012.11.020","article-title":"S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1","volume":"3","author":"Denichenko","year":"2013","journal-title":"Cell Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"13369","DOI":"10.1007\/s13277-016-5253-1","article-title":"Alternative splicing of S6K1 promotes non-small cell lung cancer survival","volume":"37","author":"Mei","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1073\/pnas.0506281103","article-title":"Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation","volume":"103","author":"Burd","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1016\/j.humpath.2008.05.008","article-title":"Expression of cyclin D1 splice variants is differentially associated with outcome in non-small cell lung cancer patients","volume":"39","author":"Li","year":"2008","journal-title":"Hum. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5628","DOI":"10.1158\/0008-5472.CAN-07-3170","article-title":"Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists","volume":"68","author":"Wang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/sj.bjc.6604308","article-title":"VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: Balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy","volume":"98","author":"Varey","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/sj.bjc.6604309","article-title":"The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice","volume":"98","author":"Rennel","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_90","first-page":"4123","article-title":"VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma","volume":"62","author":"Bates","year":"2002","journal-title":"Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/sj.bjc.6603839","article-title":"Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma","volume":"97","author":"Dunn","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1002\/ijc.26072","article-title":"Re-expression of CEACAM1 long cytoplasmic domain isoform is associated with invasion and migration of colorectal cancer","volume":"129","author":"Ieda","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.neo.2014.05.003","article-title":"CEACAM1 promotes melanoma cell growth through Sox-2","volume":"16","author":"Ortenberg","year":"2014","journal-title":"Neoplasia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.stem.2014.01.009","article-title":"CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis","volume":"14","author":"Todaro","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.3892\/or.2013.2273","article-title":"CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer","volume":"29","author":"Saito","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.5966\/sctm.2015-0048","article-title":"Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target","volume":"4","author":"Yan","year":"2015","journal-title":"Stem Cells Transl. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"9369","DOI":"10.1038\/sj.onc.1208182","article-title":"Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation","volume":"23","author":"Singh","year":"2004","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1002\/jcb.24103","article-title":"Involvement of hnRNP A1 in the matrix metalloprotease-3-dependent regulation of Rac1 pre-mRNA splicing","volume":"113","author":"Pelisch","year":"2012","journal-title":"J. Cell Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Melzer, C., Hass, R., Lehnert, H., and Ungefroren, H. (2019). RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression. Cells, 8.","DOI":"10.3390\/cells8010021"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1158\/1541-7786.MCR-08-0008","article-title":"Increased Rac1b expression sustains colorectal tumor cell survival","volume":"6","author":"Matos","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1972367","DOI":"10.1155\/2016\/1972367","article-title":"Extending the Impact of RAC1b Overexpression to Follicular Thyroid Carcinomas","volume":"2016","author":"Faria","year":"2016","journal-title":"Int. J. Endocrinol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Faria, M., Matos, P., Pereira, T., Cabrera, R., Cardoso, B.A., Bugalho, M.J., and Silva, A.L. (2017). RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172689"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1593\/neo.101744","article-title":"Identification of an exon 4-deletion variant of epidermal growth factor receptor with increased metastasis-promoting capacity","volume":"13","author":"Wang","year":"2011","journal-title":"Neoplasia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1096\/fj.11-191064","article-title":"Growth and metastasis suppression of glioma xenografts expressing exon 4-deletion variant of epidermal growth factor receptor by monoclonal antibody CH12-mediated receptor degradation","volume":"26","author":"Wang","year":"2012","journal-title":"FASEB J."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1093\/carcin\/bgt216","article-title":"Exon 4 deletion variant of epidermal growth factor receptor enhances invasiveness and cisplatin resistance in epithelial ovarian cancer","volume":"34","author":"Zhang","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1126\/scitranslmed.3004688","article-title":"KLF6-SV1 drives breast cancer metastasis and is associated with poor survival","volume":"5","author":"Hatami","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1158\/0008-5472.CAN-07-2604","article-title":"A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response","volume":"68","author":"DiFeo","year":"2008","journal-title":"Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/j.ejca.2008.06.030","article-title":"Increased alternative splicing of the KLF6 tumour suppressor gene correlates with prognosis and tumour grade in patients with pancreatic cancer","volume":"44","author":"Hartel","year":"2008","journal-title":"Eur. J. Cancer"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.1158\/0008-5472.CAN-05-0217","article-title":"Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread","volume":"65","author":"Narla","year":"2005","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1053\/j.gastro.2008.02.015","article-title":"Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma","volume":"134","author":"Yea","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"36185","DOI":"10.18632\/oncotarget.15873","article-title":"High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/1479-5876-12-136","article-title":"An aberrant spliced transcript of focal adhesion kinase is exclusively expressed in human breast cancer","volume":"12","author":"Yao","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nrc1739","article-title":"Biomarkers in cancer staging, prognosis and treatment selection","volume":"5","author":"Ludwig","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1878-5085-4-7","article-title":"Pitfalls and limitations in translation from biomarker discovery to clinical utility in predictive and personalised medicine","volume":"4","author":"Drucker","year":"2013","journal-title":"EPMA J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1101\/gad.1973010","article-title":"Alternative pre-mRNA splicing regulation in cancer: Pathways and programs unhinged","volume":"24","author":"David","year":"2010","journal-title":"Genes Dev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nsmb.1608","article-title":"Cancer-associated regulation of alternative splicing","volume":"16","author":"Venables","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Gardina, P.J., Clark, T.A., Shimada, B., Staples, M.K., Yang, Q., Veitch, J., Schweitzer, A., Awad, T., Sugnet, C., and Dee, S. (2006). Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array. BMC Genomics, 7.","DOI":"10.1186\/1471-2164-7-325"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Shapiro, I.M., Cheng, A.W., Flytzanis, N.C., Balsamo, M., Condeelis, J.S., Oktay, M.H., Burge, C.B., and Gertler, F.B. (2011). An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002218"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/MCB.00709-10","article-title":"Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer","volume":"31","author":"Cheng","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"269570","DOI":"10.1155\/2012\/269570","article-title":"Splicing programs and cancer","volume":"2012","author":"Germann","year":"2012","journal-title":"J. Nucleic Acids"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1158\/1541-7786.MCR-09-0528","article-title":"Exon-level microarray analyses identify alternative splicing programs in breast cancer","volume":"8","author":"Lapuk","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"7654","DOI":"10.1038\/srep07654","article-title":"Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer","volume":"5","author":"Qu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1038\/onc.2015.270","article-title":"Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells","volume":"35","author":"Calabretta","year":"2016","journal-title":"Oncogene"},{"key":"ref_124","first-page":"5079","article-title":"A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis","volume":"56","author":"Nagane","year":"1996","journal-title":"Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1073\/pnas.0813314106","article-title":"Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis","volume":"106","author":"Zhu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/bjc.1996.364","article-title":"Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer","volume":"74","author":"Gotley","year":"1996","journal-title":"Br. J. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0046-8177(98)80014-2","article-title":"CD44V6 expression in human colorectal carcinoma","volume":"29","author":"Coppola","year":"1998","journal-title":"Hum. Pathol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/1097-0142(20000815)89:4<733::AID-CNCR3>3.0.CO;2-#","article-title":"Decreased expression of CD44, alpha-catenin, and deleted colon carcinoma and altered expression of beta-catenin in ulcerative colitis-associated dysplasia and carcinoma, as compared with sporadic colon neoplasms","volume":"89","author":"Mikami","year":"2000","journal-title":"Cancer"},{"key":"ref_129","first-page":"1421","article-title":"Prognostic significance of relevant markers of cancer stem cells in colorectal cancer\u2014A meta analysis","volume":"59","author":"Fan","year":"2012","journal-title":"Hepatogastroenterology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1053\/j.gastro.2008.05.052","article-title":"B-Raf(V600E) cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival","volume":"135","author":"Matos","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1016\/j.ejca.2014.04.019","article-title":"RAC1b overexpression correlates with poor prognosis in KRAS\/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX\/XELOX chemotherapy","volume":"50","author":"Cuatrecasas","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1530\/EJE-12-0960","article-title":"RAC1b overexpression in papillary thyroid carcinoma: A role to unravel","volume":"168","author":"Silva","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1158\/1535-7163.MCT-18-0955","article-title":"RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer","volume":"18","author":"Goka","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Zhao, S., Fung-Leung, W.P., Bittner, A., Ngo, K., and Liu, X. (2014). Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0078644"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"7624","DOI":"10.1038\/s41598-018-26035-x","article-title":"Computational identification and validation of alternative splicing in ZSF1 rat RNA-seq data, a preclinical model for type 2 diabetic nephropathy","volume":"8","author":"Zhang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zhang, B., Lin, L.L., and Zhao, S. (2017). Evaluation and comparison of computational tools for RNA-seq isoform quantification. BMC Genom., 18.","DOI":"10.1186\/s12864-017-4002-1"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrg2484","article-title":"RNA-Seq: A revolutionary tool for transcriptomics","volume":"10","author":"Wang","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nmeth.1226","article-title":"Mapping and quantifying mammalian transcriptomes by RNA-Seq","volume":"5","author":"Mortazavi","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nrg.2016.10","article-title":"Translating RNA sequencing into clinical diagnostics: Opportunities and challenges","volume":"17","author":"Byron","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1038\/srep01689","article-title":"RNA sequencing of cancer reveals novel splicing alterations","volume":"3","author":"Eswaran","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.ygyno.2017.11.028","article-title":"Systematic profiling of alternative splicing signature reveals prognostic predictor for ovarian cancer","volume":"148","author":"Zhu","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.canlet.2017.02.016","article-title":"Prognostic alternative mRNA splicing signature in non-small cell lung cancer","volume":"393","author":"Li","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3389\/fonc.2019.00511","article-title":"Genome-Wide Profiling Reveals the Landscape of Prognostic Alternative Splicing Signatures in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Yang","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1038\/s41467-020-15815-7","article-title":"Intron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ebiom.2018.09.021","article-title":"Profiles of alternative splicing in colorectal cancer and their clinical significance: A study based on large-scale sequencing data","volume":"36","author":"Xiong","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Lian, H., Wang, A., Shen, Y., Wang, Q., Zhou, Z., Zhang, R., Li, K., Liu, C., and Jia, H. (2020). Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-01288-x"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"29929","DOI":"10.18632\/oncotarget.4966","article-title":"Stroma derived COL6A3 is a potential prognosis marker of colorectal carcinoma revealed by quantitative proteomics","volume":"6","author":"Qiao","year":"2015","journal-title":"Oncotarget"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1093\/bioinformatics\/btt606","article-title":"Inferring therapeutic targets from heterogeneous data: HKDC1 is a novel potential therapeutic target for cancer","volume":"30","author":"Li","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/s41467-017-01153-8","article-title":"Gene isoforms as expression-based biomarkers predictive of drug response in vitro","volume":"8","author":"Safikhani","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41573-019-0042-3","article-title":"Targeting mRNA processing as an anticancer strategy","volume":"19","author":"Desterro","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Rahman, M.A., Nasrin, F., Bhattacharjee, S., and Nandi, S. (2020). Hallmarks of Splicing Defects in Cancer: Clinical Applications in the Era of Personalized Medicine. Cancers, 12.","DOI":"10.3390\/cancers12061381"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/nm.4165","article-title":"Therapeutic targeting of splicing in cancer","volume":"22","author":"Lee","year":"2016","journal-title":"Nat. Med."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Antonopoulou, E., and Ladomery, M. (2018). Targeting Splicing in Prostate Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051287"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.molcel.2016.05.034","article-title":"Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing","volume":"63","author":"Aubol","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.molcel.2014.04.020","article-title":"Akt-ing up on SRPK1: Oncogene or tumor suppressor?","volume":"54","author":"Toker","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/j.ccr.2011.10.016","article-title":"WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing","volume":"20","author":"Amin","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Siqueira, R.P., Barbosa Ede, A., Poleto, M.D., Righetto, G.L., Seraphim, T.V., Salgado, R.L., Ferreira, J.G., Barros, M.V., de Oliveira, L.L., and Laranjeira, A.B. (2015). Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340). PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134882"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/bjc.2014.342","article-title":"Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma","volume":"111","author":"Gammons","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.chembiol.2018.01.013","article-title":"SRPKIN-1: A Covalent SRPK1\/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform","volume":"25","author":"Hatcher","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"24246","DOI":"10.1074\/jbc.M314298200","article-title":"Manipulation of alternative splicing by a newly developed inhibitor of Clks","volume":"279","author":"Muraki","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1021\/jm200274d","article-title":"Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: Modulation of alternative pre-RNA splicing","volume":"54","author":"Debdab","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"e8289","DOI":"10.15252\/emmm.201708289","article-title":"Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability","volume":"10","author":"Iwai","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Araki, S., Dairiki, R., Nakayama, Y., Murai, A., Miyashita, R., Iwatani, M., Nomura, T., and Nakanishi, O. (2015). Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116929"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1002\/cncr.31398","article-title":"Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome","volume":"124","author":"Assi","year":"2018","journal-title":"Cancer"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1158\/1078-0432.CCR-06-0249","article-title":"A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer","volume":"13","author":"Talbot","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1517\/13543784.12.2.283","article-title":"Indisulam: An anticancer sulfonamide in clinical development","volume":"12","author":"Supuran","year":"2003","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"eaal3755","DOI":"10.1126\/science.aal3755","article-title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15","volume":"356","author":"Han","year":"2017","journal-title":"Science"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/nchembio.2363","article-title":"Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides","volume":"13","author":"Uehara","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"194395","DOI":"10.1016\/j.bbagrm.2019.06.006","article-title":"More than a messenger: Alternative splicing as a therapeutic target","volume":"1862","author":"Black","year":"2019","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.molcel.2013.12.018","article-title":"Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer","volume":"53","author":"Sanidas","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"12270","DOI":"10.1093\/nar\/gkx831","article-title":"hnRNPM guides an alternative splicing program in response to inhibition of the PI3K\/AKT\/mTOR pathway in Ewing sarcoma cells","volume":"45","author":"Passacantilli","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1073\/pnas.75.1.285","article-title":"Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide","volume":"75","author":"Stephenson","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1073\/pnas.75.1.280","article-title":"Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide","volume":"75","author":"Zamecnik","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"9087","DOI":"10.1038\/sj.onc.1207231","article-title":"Antisense oligonucleotide-based therapeutics for cancer","volume":"22","author":"Dean","year":"2003","journal-title":"Oncogene"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1056\/NEJMra1705346","article-title":"Treating Disease at the RNA Level with Oligonucleotides","volume":"380","author":"Levin","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev-med-041217-010829","article-title":"Therapeutic Antisense Oligonucleotides Are Coming of Age","volume":"70","author":"Bennett","year":"2019","journal-title":"Annu Rev. Med."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"104550","DOI":"10.1016\/j.phrs.2019.104550","article-title":"RNA-based therapeutics for colorectal cancer: Updates and future directions","volume":"152","author":"Liu","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"6549","DOI":"10.1093\/nar\/gkw533","article-title":"Splice-switching antisense oligonucleotides as therapeutic drugs","volume":"44","author":"Havens","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/nat.2016.0657","article-title":"FDA Approves Eteplirsen for Duchenne Muscular Dystrophy: The Next Chapter in the Eteplirsen Saga","volume":"27","author":"Krieg","year":"2017","journal-title":"Nucleic Acid Ther."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1212\/WNL.0000000000006502","article-title":"Evidence in focus: Nusinersen use in spinal muscular atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology","volume":"91","author":"Michelson","year":"2018","journal-title":"Neurology"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"e2146","DOI":"10.1212\/WNL.0000000000005680","article-title":"Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production","volume":"90","author":"Charleston","year":"2018","journal-title":"Neurology"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"16411","DOI":"10.1074\/jbc.M009256200","article-title":"Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death","volume":"276","author":"Mercatante","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4161\/bbug.2.3.15165","article-title":"Modulation of RNA splicing as a potential treatment for cancer","volume":"2","author":"Bauman","year":"2011","journal-title":"Bioeng. Bugs"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"8977","DOI":"10.1158\/0008-5472.CAN-10-2513","article-title":"Turning on a fuel switch of cancer: hnRNP proteins regulate alternative splicing of pyruvate kinase mRNA","volume":"70","author":"Chen","year":"2010","journal-title":"Cancer Res."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"120133","DOI":"10.1098\/rsob.120133","article-title":"Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides","volume":"2","author":"Wang","year":"2012","journal-title":"Open Biol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1038\/s41467-019-09523-0","article-title":"Specific inhibition of splicing factor activity by decoy RNA oligonucleotides","volume":"10","author":"Denichenko","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_187","first-page":"5536","article-title":"Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors","volume":"55","author":"Moscatello","year":"1995","journal-title":"Cancer Res."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1093\/jnen\/63.7.700","article-title":"Immunohistochemical detection of EGFRvIII in high malignancy grade astrocytomas and evaluation of prognostic significance","volume":"63","author":"Aldape","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"679","DOI":"10.2217\/imt.14.21","article-title":"Rindopepimut: A promising immunotherapeutic for the treatment of glioblastoma multiforme","volume":"6","author":"Swartz","year":"2014","journal-title":"Immunotherapy"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1158\/1078-0432.CCR-06-1453","article-title":"The efficacy of epidermal growth factor receptor-specific antibodies against glioma xenografts is influenced by receptor levels, activation status, and heterodimerization","volume":"13","author":"Johns","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1111\/j.1349-7006.2008.00945.x","article-title":"Antitumor activity of cetuximab against malignant glioma cells overexpressing EGFR deletion mutant variant III","volume":"99","author":"Fukai","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_192","first-page":"3496","article-title":"Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa)","volume":"8","author":"Heimberger","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.ejca.2010.02.024","article-title":"CD44, a therapeutic target for metastasising tumours","volume":"46","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_194","first-page":"3961S","article-title":"Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma","volume":"9","author":"Borjesson","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1007\/s00262-003-0396-5","article-title":"Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck","volume":"52","author":"Colnot","year":"2003","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"6064","DOI":"10.1158\/1078-0432.CCR-06-0910","article-title":"A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus","volume":"12","author":"Tijink","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.oraloncology.2007.10.009","article-title":"Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma","volume":"44","author":"Riechelmann","year":"2008","journal-title":"Oral Oncol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"7624","DOI":"10.1158\/1078-0432.CCR-08-1547","article-title":"Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development","volume":"14","author":"Sahin","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13045-017-0473-4","article-title":"Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer","volume":"10","author":"Singh","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.chembiol.2014.09.001","article-title":"Small-molecule inhibitors of protein-protein interactions: Progressing toward the reality","volume":"21","author":"Arkin","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev-pharmtox-011613-140028","article-title":"Targeting protein-protein interaction by small molecules","volume":"54","author":"Jin","year":"2014","journal-title":"Annu Rev. Pharmacol. Toxicol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets","volume":"19","author":"Souers","year":"2013","journal-title":"Nat. Med."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1021\/jm501092z","article-title":"Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment","volume":"58","author":"Zhao","year":"2015","journal-title":"J. Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9032\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:38:36Z","timestamp":1760179116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,27]]},"references-count":203,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21239032"],"URL":"https:\/\/doi.org\/10.3390\/ijms21239032","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,27]]}}}