{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T07:18:37Z","timestamp":1785395917282,"version":"3.56.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alternative splicing (AS), a critical post-transcriptional regulatory mechanism, expands gene expression patterns, thereby leading to increased protein diversity. Indeed, more than 95% of human genes undergo alternative splicing events (ASEs). In this study, we drew an all-around AS profile of thyroid cancer cells based on RNA-seq data. In total, there were 45,150 AS in 10,446 thyroid cancer cell genes derived from 506 patients, suggesting that ASEs is a common process in TC. Moreover, 1819 AS signatures were found to be significantly associated with the overall survival (OS) of TC patients. Kaplan\u2013Meier survival analyses suggested that seven types of ASEs were associated with poor prognosis of TC (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Among them, exon skipping (ES) was the most common, with alternate promoter (AP) and alternate terminator (AT) coming second and third, respectively. Our results indicated that acceptor sites (AA) (AUC: 0.937), alternate donor sites (AD) (AUC: 0.965), AT (AUC: 0.964), ES (AUC: 0.999), mutually exclusive exons (ME) (AUC: 0.999), and retained intron (RI) (AUC: 0.837) exhibited an AUC greater than 0.6. In addition, age and risk score (All) were risk factors for TC patients. We also evaluated whether TC-ASEs are regulated by various splicing factors (SFs). We found that the expression of 90 SFs was associated with 469 ASEs and OS of TC patients. Our findings provide an insight into the role of spliceosomes in TC, which may offer novel perspectives in tumor research.<\/jats:p>","DOI":"10.1038\/s41598-021-84403-6","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T11:07:32Z","timestamp":1614596852000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Alternative splicing events implicated in carcinogenesis and prognosis of thyroid gland cancer"],"prefix":"10.1038","volume":"11","author":[{"given":"Zeng-Hong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,1]]},"reference":[{"key":"84403_CR1","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/s41574-018-0080-7","volume":"14","author":"TS Wang","year":"2018","unstructured":"Wang, T. S. & Sosa, J. A. Thyroid surgery for differentiated thyroid cancer-recent advances and future directions. Nat. Rev. Endocrinol. 14, 670\u2013683 (2018).","journal-title":"Nat. Rev. Endocrinol."},{"key":"84403_CR2","doi-asserted-by":"publisher","first-page":"242","DOI":"10.5694\/j.1326-5377.2004.tb05894.x","volume":"180","author":"EJ Mackenzie","year":"2004","unstructured":"Mackenzie, E. J. & MortiMer, R. H. Thyroid nodules and thyroid cancer. Med. J. Aust 180, 242\u2013247 (2004).","journal-title":"Med. J. Aust"},{"key":"84403_CR3","doi-asserted-by":"publisher","first-page":"E276","DOI":"10.1210\/jc.2013-2503","volume":"99","author":"CK Jung","year":"2014","unstructured":"Jung, C. K. et al. The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. J. Clin. Endocrinol. Metab. 99, E276\u2013E285 (2014).","journal-title":"J. Clin. Endocrinol. Metab."},{"issue":"7","key":"84403_CR4","first-page":"2856","volume":"23","author":"J Zhu","year":"2019","unstructured":"Zhu, J. et al. MiR-506 suppresses papillary thyroid carcinoma cell proliferation and metastasis via targeting IL17RD. Eur. Rev. Med. Pharmacol. Sci. 23(7), 2856\u20132862 (2019).","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"84403_CR5","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s12022-009-9069-z","volume":"20","author":"MN NiKiForova","year":"2009","unstructured":"NiKiForova, M. N., ChiosEa, S. I. & NiKiForov, Y. E. MicroRNA expression profiles in thyroid tumors. Endocr. Pathol. 20, 85\u201391 (2009).","journal-title":"Endocr. Pathol."},{"key":"84403_CR6","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1089\/thy.2012.0532","volume":"23","author":"LH Veiga","year":"2013","unstructured":"Veiga, L. H., Neta, G., Gschebrook-KilfoY, B., Ron, E. & Devesa, S. S. Thyroid cancer incidence patterns in Sao Paulo, Brazil, and the U.S. SEER program, 1997\u20132008. Thyroid 23, 748\u2013757 (2013).","journal-title":"Thyroid"},{"key":"84403_CR7","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.ctrv.2014.01.002","volume":"40","author":"E Frohlich","year":"2014","unstructured":"Frohlich, E. & Wahl, R. The current role of targeted therapies to induce radioiodine uptake in thyroid cancer. Cancer Treat. Rev. 40, 665\u2013674 (2014).","journal-title":"Cancer Treat. Rev."},{"issue":"7280","key":"84403_CR8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nature08909","volume":"463","author":"TW Nilsen","year":"2010","unstructured":"Nilsen, T. W. & Graveley, B. R. Expansion of the eukaryotic proteome by alternative splicing. Nature 463(7280), 457\u2013463 (2010).","journal-title":"Nature"},{"key":"84403_CR9","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1080\/21541264.2016.1268245","volume":"8","author":"B Singh","year":"2017","unstructured":"Singh, B. & Eyras, E. The role of alternative splicing in cancer. Transcription 8, 91\u201398 (2017).","journal-title":"Transcription"},{"issue":"9","key":"84403_CR10","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1016\/j.celrep.2017.08.012","volume":"20","author":"H Climente-Gonz\u00e1lez","year":"2017","unstructured":"Climente-Gonz\u00e1lez, H., Porta-Pardo, E., Godzik, A. & Eyras, E. The functional impact of alternative splicing in cancer. Cell Rep. 20(9), 2215\u20132226 (2017).","journal-title":"Cell Rep."},{"issue":"46","key":"84403_CR11","doi-asserted-by":"publisher","first-page":"5311","DOI":"10.1038\/onc.2013.533","volume":"33","author":"S Oltean","year":"2014","unstructured":"Oltean, S. & Bates, D. O. Hallmarks of alternative splicing in cancer. Oncogene 33(46), 5311\u20135318 (2014).","journal-title":"Oncogene"},{"issue":"11","key":"84403_CR12","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41577-019-0195-7","volume":"19","author":"L Frankiw","year":"2019","unstructured":"Frankiw, L., Baltimore, D. & Li, G. Alternative mRNA splicing in cancer immunotherapy. Nat. Rev. Immunol. 19(11), 675\u2013687 (2019).","journal-title":"Nat. Rev. Immunol."},{"issue":"2","key":"84403_CR13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.ccell.2018.07.001","volume":"34","author":"A Kahles","year":"2018","unstructured":"Kahles, A. et al. Comprehensive analysis of alternative splicing across tumors from 8,705 patients. Cancer Cell 34(2), 211-224.e6 (2018).","journal-title":"Cancer Cell"},{"issue":"40","key":"84403_CR14","doi-asserted-by":"publisher","first-page":"6678","DOI":"10.1038\/s41388-019-0910-7","volume":"38","author":"Y Zhang","year":"2019","unstructured":"Zhang, Y. et al. Pan-cancer analysis of clinical relevance of alternative splicing events in 31 human cancers. Oncogene 38(40), 6678\u20136695 (2019).","journal-title":"Oncogene"},{"key":"84403_CR15","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/nature07509","volume":"456","author":"ET Wang","year":"2008","unstructured":"Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470\u2013476 (2008).","journal-title":"Nature"},{"key":"84403_CR16","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.7150\/jca.24569","volume":"9","author":"J Liu","year":"2018","unstructured":"Liu, J. et al. Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer. J. Cancer 9, 1754\u20131764 (2018).","journal-title":"J. Cancer"},{"key":"84403_CR17","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ebiom.2018.07.040","volume":"34","author":"P Lin","year":"2018","unstructured":"Lin, P. et al. Systematic analysis of survival-associated alternative splicing signatures in gastrointestinal pan-adenocarcinomas. EBioMedicine 34, 46\u201360 (2018).","journal-title":"EBioMedicine"},{"key":"84403_CR18","first-page":"2473","volume":"53","author":"ZG Huang","year":"2018","unstructured":"Huang, Z. G., He, R. Q. & Mo, Z. N. Prognostic value and potential function of splicing events in prostate adenocarcinoma. Int. J. Oncol. 53, 2473\u20132487 (2018).","journal-title":"Int. J. Oncol."},{"key":"84403_CR19","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1159\/000492094","volume":"48","author":"RQ He","year":"2018","unstructured":"He, R. Q. et al. Prognostic signature of alternative splicing events in bladder urothelial carcinoma based on spliceseq data from 317 cases. Cell Physiol. Biochem. 48, 1355\u20131368 (2018).","journal-title":"Cell Physiol. Biochem."},{"issue":"7","key":"84403_CR20","first-page":"4010","volume":"11","author":"ZC Xie","year":"2019","unstructured":"Xie, Z. C. et al. Prognostic alternative splicing signatures and underlying regulatory network in esophageal carcinoma. Am. J. Transl. Res. 11(7), 4010\u20134028 (2019).","journal-title":"Am. J. Transl. Res."},{"key":"84403_CR21","first-page":"2686875","volume":"2019","author":"C Wang","year":"2019","unstructured":"Wang, C. et al. Whole genome analysis and prognostic model construction based on alternative splicing events in endometrial cancer. Biomed. Res. Int. 2019, 2686875 (2019).","journal-title":"Biomed. Res. Int."},{"issue":"13","key":"84403_CR22","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.18632\/aging.102085","volume":"11","author":"QF Chen","year":"2019","unstructured":"Chen, Q. F., Li, W., Wu, P., Shen, L. & Huang, Z. L. Alternative splicing events are prognostic in hepatocellular carcinoma. Aging (Albany NY). 11(13), 4720\u20134735 (2019).","journal-title":"Aging (Albany NY)."},{"issue":"7","key":"84403_CR23","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.18632\/aging.101902","volume":"11","author":"P Lin","year":"2019","unstructured":"Lin, P. et al. Role of global aberrant alternative splicing events in papillary thyroid cancer prognosis. Aging (Albany NY). 11(7), 2082\u20132097 (2019).","journal-title":"Aging (Albany NY)."},{"issue":"D1","key":"84403_CR24","doi-asserted-by":"publisher","first-page":"D1018","DOI":"10.1093\/nar\/gkv1288","volume":"44","author":"M Ryan","year":"2016","unstructured":"Ryan, M. et al. TCGASpliceSeq a compendium of alternative mRNA splicing in cancer. Nucleic Acids Res. 44(D1), D1018\u2013D1022 (2016).","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"84403_CR25","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.celrep.2018.01.088","volume":"23","author":"M Seiler","year":"2018","unstructured":"Seiler, M. et al. Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types. Cell Rep. 23(1), 282\u2013296 (2018).","journal-title":"Cell Rep."},{"key":"84403_CR26","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1093\/bioinformatics\/btx364","volume":"33","author":"JR Conway","year":"2017","unstructured":"Conway, J. R., Lex, A. & Gehlenborg, N. UpSetR: an R package for the visualization of intersecting sets and their properties. Bioinformatics 33, 2938\u20132940 (2017).","journal-title":"Bioinformatics"},{"key":"84403_CR27","doi-asserted-by":"publisher","first-page":"5512","DOI":"10.1002\/sim.3148","volume":"26","author":"W Sauerbrei","year":"2007","unstructured":"Sauerbrei, W., Royston, P. & Binder, H. Selection of important variables and determination of functional form for continuous predictors in multivariable model building. Stat. Med. 26, 5512\u20135528 (2007).","journal-title":"Stat. Med."},{"key":"84403_CR28","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1093\/neuonc\/now285","volume":"19","author":"X Hu","year":"2017","unstructured":"Hu, X. et al. Multigene signature for predicting prognosis of patients with 1p19q codeletion diffuse glioma. Neuro Oncol. 19, 786\u2013795 (2017).","journal-title":"Neuro Oncol."},{"issue":"W1","key":"84403_CR29","doi-asserted-by":"publisher","first-page":"W556","DOI":"10.1093\/nar\/gkz430","volume":"47","author":"Z Tang","year":"2019","unstructured":"Tang, Z., Kang, B., Li, C., Chen, T. & Zhang, Z. GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 47(W1), W556\u2013W560 (2019).","journal-title":"Nucleic Acids Res."},{"issue":"9","key":"84403_CR30","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s00439-017-1803-x","volume":"136","author":"I Kozlovski","year":"2017","unstructured":"Kozlovski, I., Siegfried, Z., Amar-Schwartz, A. & Karni, R. The role of RNA alternative splicing in regulating cancer metabolism. Hum. Genet. 136(9), 1113\u20131127 (2017).","journal-title":"Hum. Genet."},{"issue":"5","key":"84403_CR31","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1517\/17425255.2015.993316","volume":"11","author":"A Wojtuszkiewicz","year":"2015","unstructured":"Wojtuszkiewicz, A. et al. Pre-mRNA splicing in cancer: The relevance in oncogenesis, treatment and drug resistance. Expert Opin. Drug Metab. Toxicol. 11(5), 673\u2013689 (2015).","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"issue":"11","key":"84403_CR32","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3390\/cancers10110458","volume":"10","author":"BD Wang","year":"2018","unstructured":"Wang, B. D. & Lee, N. H. Aberrant RNA splicing in cancer and drug resistance. Cancers 10(11), 458 (2018).","journal-title":"Cancers"},{"key":"84403_CR33","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.molcel.2005.10.026","volume":"20","author":"C Ghigna","year":"2005","unstructured":"Ghigna, C. et al. Cell motility is controlled by SF2\/ASF through alternative splicing of the Ron protooncogene. Mol. Cell 20, 881\u2013890 (2005).","journal-title":"Mol. Cell"},{"key":"84403_CR34","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nsmb1209","volume":"14","author":"R Karni","year":"2007","unstructured":"Karni, R. et al. The gene encoding the splicing factor SF2\/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14, 185\u2013193 (2007).","journal-title":"Nat. Struct. Mol. Biol."},{"issue":"45","key":"84403_CR35","doi-asserted-by":"publisher","first-page":"7106","DOI":"10.1038\/s41388-019-0936-x","volume":"38","author":"L Piqu\u00e9","year":"2019","unstructured":"Piqu\u00e9, L. et al. Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer. Oncogene 38(45), 7106\u20137112 (2019).","journal-title":"Oncogene"},{"key":"84403_CR36","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1002\/jcb.29314","volume":"12","author":"Y Duan","year":"2020","unstructured":"Duan, Y. & Zhang, D. Identification of novel prognostic alternative splicing signature in papillary renal cell carcinoma. J. Cell Biochem. 12, 672\u2013689 (2020).","journal-title":"J. Cell Biochem."},{"key":"84403_CR37","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1053\/jhep.2001.25387","volume":"34","author":"T Takehara","year":"2001","unstructured":"Takehara, T., Liu, X., Fujimoto, J., Friedman, S. L. & Takahashi, H. Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology 34, 55\u201361 (2001).","journal-title":"Hepatology"},{"key":"84403_CR38","doi-asserted-by":"publisher","first-page":"49374","DOI":"10.1074\/jbc.M209236200","volume":"277","author":"DR Mercatante","year":"2002","unstructured":"Mercatante, D. R., Mohler, J. L. & Kole, R. Cellular response to an antisense-mediated shift of Bcl-x pre-mRNA splicing and antineoplastic agents. J. Biol. Chem. 277, 49374\u201349382 (2002).","journal-title":"J. Biol. Chem."},{"issue":"21","key":"84403_CR39","doi-asserted-by":"publisher","first-page":"e01048","DOI":"10.1128\/JVI.01048-19","volume":"93","author":"SB Kutluay","year":"2019","unstructured":"Kutluay, S. B. et al. Genome-wide analysis of heterogeneous nuclear ribonucleoprotein (hnRNP) binding to HIV-1 RNA reveals a key role for hnRNP H1 in alternative viral mRNA splicing. J. Virol. 93(21), e01048-e1119 (2019).","journal-title":"J. Virol."},{"issue":"9","key":"84403_CR40","doi-asserted-by":"publisher","first-page":"956","DOI":"10.15252\/embr.201438679","volume":"15","author":"Y Oka","year":"2014","unstructured":"Oka, Y. et al. UBL5 is essential for pre-mRNA splicing and sister chromatid cohesion in human cells. EMBO Rep. 15(9), 956\u2013964 (2014).","journal-title":"EMBO Rep."},{"issue":"1","key":"84403_CR41","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1042\/BJ20080847","volume":"416","author":"F Xu","year":"2008","unstructured":"Xu, F. et al. Disruption of a mitochondrial RNA-binding protein gene results in decreased cytochrome b expression and a marked reduction in ubiquinol-cytochrome c reductase activity in mouse heart mitochondria. Biochem. J. 416(1), 15\u201326 (2008).","journal-title":"Biochem. J."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84403-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84403-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84403-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T04:28:38Z","timestamp":1670041718000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84403-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,1]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["84403"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-84403-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,1]]},"assertion":[{"value":"7 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4841"}}