{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T15:18:27Z","timestamp":1748963907671,"version":"3.37.3"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21CA202417","R01CA128813"],"award-info":[{"award-number":["R21CA202417","R01CA128813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP\u2013SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 <jats:italic>KLK3<\/jats:italic> SNPs, and 1083 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20093.5\u2009\u00d7\u200910<jats:sup>\u20139<\/jats:sup>) and 3145 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20091\u2009\u00d7\u200910<jats:sup>\u20135<\/jats:sup>) SNP\u2013SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved <jats:italic>KLK3<\/jats:italic>. The 3 most common gene\u2013gene interactions were <jats:italic>KLK3-COL4A1:COL4A2<\/jats:italic>, <jats:italic>KLK3-CDH13,<\/jats:italic> and <jats:italic>KLK3-TGFBR3.<\/jats:italic> Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified <jats:italic>KLK3<\/jats:italic> SNP\u2013SNP interactions were supported by gene expression and protein\u2013protein interaction results. Our findings suggest <jats:italic>KLK3<\/jats:italic> SNP interactions may play an important role in PCa aggressiveness.<\/jats:p>","DOI":"10.1038\/s41598-021-85169-7","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T10:05:37Z","timestamp":1619690737000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["KLK3 SNP\u2013SNP interactions for prediction of prostate cancer aggressiveness"],"prefix":"10.1038","volume":"11","author":[{"given":"Hui-Yi","family":"Lin","sequence":"first","affiliation":[]},{"given":"Po-Yu","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Chia-Ho","family":"Cheng","sequence":"additional","affiliation":[]},{"given":"Heng-Yuan","family":"Tung","sequence":"additional","affiliation":[]},{"given":"Zhide","family":"Fang","sequence":"additional","affiliation":[]},{"given":"Anders E.","family":"Berglund","sequence":"additional","affiliation":[]},{"given":"Ann","family":"Chen","sequence":"additional","affiliation":[]},{"given":"Jennifer","family":"French-Kwawu","sequence":"additional","affiliation":[]},{"given":"Darian","family":"Harris","sequence":"additional","affiliation":[]},{"given":"Julio","family":"Pow-Sang","sequence":"additional","affiliation":[]},{"given":"Kosj","family":"Yamoah","sequence":"additional","affiliation":[]},{"given":"John L.","family":"Cleveland","sequence":"additional","affiliation":[]},{"given":"Shivanshu","family":"Awasthi","sequence":"additional","affiliation":[]},{"given":"Robert J.","family":"Rounbehler","sequence":"additional","affiliation":[]},{"given":"Travis","family":"Gerke","sequence":"additional","affiliation":[]},{"given":"Jasreman","family":"Dhillon","sequence":"additional","affiliation":[]},{"given":"Rosalind","family":"Eeles","sequence":"additional","affiliation":[]},{"given":"Zsofia","family":"Kote-Jarai","sequence":"additional","affiliation":[]},{"given":"Kenneth","family":"Muir","sequence":"additional","affiliation":[]},{"name":"UKGPCS collaborators","sequence":"additional","affiliation":[]},{"given":"Rosalind","family":"Eeles","sequence":"additional","affiliation":[]},{"given":"Zsofia","family":"Kote-Jarai","sequence":"additional","affiliation":[]},{"given":"Kenneth","family":"Muir","sequence":"additional","affiliation":[]},{"given":"Johanna","family":"Schleutker","sequence":"additional","affiliation":[]},{"given":"Nora","family":"Pashayan","sequence":"additional","affiliation":[]},{"name":"APCB (Australian Prostate Cancer BioResource)","sequence":"additional","affiliation":[]},{"given":"Judith","family":"Clements","sequence":"additional","affiliation":[]},{"given":"Jyotsna","family":"Batra","sequence":"additional","affiliation":[]},{"given":"David E.","family":"Neal","sequence":"additional","affiliation":[]},{"given":"Sune F.","family":"Nielsen","sequence":"additional","affiliation":[]},{"given":"B\u00f8rge G.","family":"Nordestgaard","sequence":"additional","affiliation":[]},{"given":"Henrik","family":"Gronberg","sequence":"additional","affiliation":[]},{"given":"Fredrik","family":"Wiklund","sequence":"additional","affiliation":[]},{"given":"Graham G.","family":"Giles","sequence":"additional","affiliation":[]},{"given":"Christopher A.","family":"Haiman","sequence":"additional","affiliation":[]},{"given":"Ruth C.","family":"Travis","sequence":"additional","affiliation":[]},{"given":"Janet L.","family":"Stanford","sequence":"additional","affiliation":[]},{"given":"Adam S.","family":"Kibel","sequence":"additional","affiliation":[]},{"given":"Cezary","family":"Cybulski","sequence":"additional","affiliation":[]},{"given":"Kay-Tee","family":"Khaw","sequence":"additional","affiliation":[]},{"given":"Christiane","family":"Maier","sequence":"additional","affiliation":[]},{"given":"Stephen N.","family":"Thibodeau","sequence":"additional","affiliation":[]},{"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[]},{"given":"Lisa","family":"Cannon-Albright","sequence":"additional","affiliation":[]},{"given":"Hermann","family":"Brenner","sequence":"additional","affiliation":[]},{"given":"Radka","family":"Kaneva","sequence":"additional","affiliation":[]},{"given":"Hardev","family":"Pandha","sequence":"additional","affiliation":[]},{"name":"The PRACTICAL consortium","sequence":"additional","affiliation":[]},{"given":"Hui-Yi","family":"Lin","sequence":"additional","affiliation":[]},{"given":"Rosalind","family":"Eeles","sequence":"additional","affiliation":[]},{"given":"Zsofia","family":"Kote-Jarai","sequence":"additional","affiliation":[]},{"given":"Kenneth","family":"Muir","sequence":"additional","affiliation":[]},{"given":"Johanna","family":"Schleutker","sequence":"additional","affiliation":[]},{"given":"Nora","family":"Pashayan","sequence":"additional","affiliation":[]},{"given":"David E.","family":"Neal","sequence":"additional","affiliation":[]},{"given":"Sune F.","family":"Nielsen","sequence":"additional","affiliation":[]},{"given":"B\u00f8rge G.","family":"Nordestgaard","sequence":"additional","affiliation":[]},{"given":"Henrik","family":"Gronberg","sequence":"additional","affiliation":[]},{"given":"Fredrik","family":"Wiklund","sequence":"additional","affiliation":[]},{"given":"Graham G.","family":"Giles","sequence":"additional","affiliation":[]},{"given":"Christopher A.","family":"Haiman","sequence":"additional","affiliation":[]},{"given":"Ruth C.","family":"Travis","sequence":"additional","affiliation":[]},{"given":"Janet L.","family":"Stanford","sequence":"additional","affiliation":[]},{"given":"Adam S.","family":"Kibel","sequence":"additional","affiliation":[]},{"given":"Cezary","family":"Cybulski","sequence":"additional","affiliation":[]},{"given":"Kay-Tee","family":"Khaw","sequence":"additional","affiliation":[]},{"given":"Christiane","family":"Maier","sequence":"additional","affiliation":[]},{"given":"Stephen N.","family":"Thibodeau","sequence":"additional","affiliation":[]},{"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[]},{"given":"Lisa","family":"Cannon-Albright","sequence":"additional","affiliation":[]},{"given":"Hermann","family":"Brenner","sequence":"additional","affiliation":[]},{"given":"Radka","family":"Kaneva","sequence":"additional","affiliation":[]},{"given":"Hardev","family":"Pandha","sequence":"additional","affiliation":[]},{"given":"Srilakshmi","family":"Srinivasan","sequence":"additional","affiliation":[]},{"given":"Judith","family":"Clements","sequence":"additional","affiliation":[]},{"given":"Jyotsna","family":"Batra","sequence":"additional","affiliation":[]},{"given":"Jong Y.","family":"Park","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"85169_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 71, 7\u201333. https:\/\/doi.org\/10.3322\/caac.21654 (2021).","journal-title":"CA Cancer J. Clin."},{"key":"85169_CR2","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1016\/S0140-6736(08)60729-1","volume":"371","author":"JE Damber","year":"2008","unstructured":"Damber, J. E. & Aus, G. Prostate cancer. Lancet 371, 1710\u20131721 (2008).","journal-title":"Lancet"},{"key":"85169_CR3","unstructured":"Albertsen, P. C. PSA and the conservative treatment of early prostate cancer. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica 78, 152\u2013153 (2006)."},{"key":"85169_CR4","doi-asserted-by":"publisher","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","volume":"45","author":"J MacArthur","year":"2017","unstructured":"MacArthur, J. et al. The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res. 45, D896\u2013D901. https:\/\/doi.org\/10.1093\/nar\/gkw1133 (2017).","journal-title":"Nucleic Acids Res."},{"key":"85169_CR5","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx084","author":"DV Conti","year":"2017","unstructured":"Conti, D. V. et al. Two novel susceptibility loci for prostate cancer in men of african ancestry. J. Natl. Cancer Inst. https:\/\/doi.org\/10.1093\/jnci\/djx084 (2017).","journal-title":"J. Natl. Cancer Inst."},{"key":"85169_CR6","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41588-018-0142-8","volume":"50","author":"FR Schumacher","year":"2018","unstructured":"Schumacher, F. R. et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat. Genet. 50, 928\u2013936. https:\/\/doi.org\/10.1038\/s41588-018-0142-8 (2018).","journal-title":"Nat. Genet."},{"key":"85169_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41391-020-00311-2","author":"RA Karunamuni","year":"2021","unstructured":"Karunamuni, R. A. et al. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer. Prostate Cancer Prostat. Dis. https:\/\/doi.org\/10.1038\/s41391-020-00311-2 (2021).","journal-title":"Prostate Cancer Prostat. Dis."},{"key":"85169_CR8","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nrg2579","volume":"10","author":"HJ Cordell","year":"2009","unstructured":"Cordell, H. J. Detecting gene\u2013gene interactions that underlie human diseases. Nat. Rev. Genet. 10, 392\u2013404 (2009).","journal-title":"Nat. Rev. Genet."},{"key":"85169_CR9","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1093\/bioinformatics\/btw762","volume":"33","author":"HY Lin","year":"2017","unstructured":"Lin, H. Y. et al. SNP interaction pattern identifier (SIPI): An intensive search for SNP\u2013SNP interaction patterns. Bioinformatics 33, 822\u2013833. https:\/\/doi.org\/10.1093\/bioinformatics\/btw762 (2017).","journal-title":"Bioinformatics"},{"key":"85169_CR10","doi-asserted-by":"publisher","first-page":"4141","DOI":"10.1093\/bioinformatics\/bty461","volume":"34","author":"HY Lin","year":"2018","unstructured":"Lin, H. Y. et al. AA9int: SNP interaction pattern search using non-hierarchical additive model set. Bioinformatics 34, 4141\u20134150. https:\/\/doi.org\/10.1093\/bioinformatics\/bty461 (2018).","journal-title":"Bioinformatics"},{"key":"85169_CR11","doi-asserted-by":"publisher","first-page":"3114","DOI":"10.1158\/0008-5472.CAN-05-3750","volume":"66","author":"T Fukumori","year":"2006","unstructured":"Fukumori, T. et al. Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. Cancer Res. 66, 3114\u20133119. https:\/\/doi.org\/10.1158\/0008-5472.CAN-05-3750 (2006).","journal-title":"Cancer Res."},{"key":"85169_CR12","doi-asserted-by":"publisher","first-page":"3068","DOI":"10.1182\/blood-2006-01-012369","volume":"108","author":"L Poliseno","year":"2006","unstructured":"Poliseno, L. et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 108, 3068\u20133071. https:\/\/doi.org\/10.1182\/blood-2006-01-012369 (2006).","journal-title":"Blood"},{"key":"85169_CR13","doi-asserted-by":"publisher","first-page":"e59688","DOI":"10.1371\/journal.pone.0059688","volume":"8","author":"HY Lin","year":"2013","unstructured":"Lin, H. Y. et al. SNP\u2013SNP interaction network in angiogenesis genes associated with prostate cancer aggressiveness. PLoS ONE 8, e59688. https:\/\/doi.org\/10.1371\/journal.pone.0059688 (2013).","journal-title":"PLoS ONE"},{"key":"85169_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092382","author":"C Sarkar","year":"2020","unstructured":"Sarkar, C., Goswami, S., Basu, S. & Chakroborty, D. Angiogenesis inhibition in prostate cancer: An update. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers12092382 (2020).","journal-title":"Cancers (Basel)."},{"key":"85169_CR15","doi-asserted-by":"publisher","first-page":"7658","DOI":"10.1158\/1078-0432.CCR-05-0460","volume":"11","author":"JL Boddy","year":"2005","unstructured":"Boddy, J. L. et al. The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer. Clin. Cancer Res. 11, 7658\u20137663. https:\/\/doi.org\/10.1158\/1078-0432.CCR-05-0460 (2005).","journal-title":"Clin. Cancer Res."},{"key":"85169_CR16","doi-asserted-by":"publisher","DOI":"10.3390\/cancers9040032","author":"K Eisermann","year":"2017","unstructured":"Eisermann, K. & Fraizer, G. The androgen receptor and VEGF: Mechanisms of androgen-regulated angiogenesis in prostate cancer. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers9040032 (2017).","journal-title":"Cancers (Basel)."},{"key":"85169_CR17","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1200\/JCO.2015.65.3154","volume":"34","author":"RR McKay","year":"2016","unstructured":"McKay, R. R. et al. A randomized phase II trial of short-course androgen deprivation therapy with or without bevacizumab for patients with recurrent prostate cancer after definitive local therapy. J. Clin. Oncol. 34, 1913\u20131920. https:\/\/doi.org\/10.1200\/JCO.2015.65.3154 (2016).","journal-title":"J. Clin. Oncol."},{"key":"85169_CR18","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1158\/0008-5472.CAN-16-1204","volume":"77","author":"E Audet-Walsh","year":"2017","unstructured":"Audet-Walsh, E. et al. Androgen-dependent repression of ERRgamma reprograms metabolism in prostate cancer. Cancer Res. 77, 378\u2013389. https:\/\/doi.org\/10.1158\/0008-5472.CAN-16-1204 (2017).","journal-title":"Cancer Res."},{"key":"85169_CR19","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/aja.2012.160","volume":"15","author":"EK Amankwah","year":"2013","unstructured":"Amankwah, E. K. et al. miR-21, miR-221 and miR-222 expression and prostate cancer recurrence among obese and non-obese cases. Asian J. Androl. 15, 226\u2013230. https:\/\/doi.org\/10.1038\/aja.2012.160 (2013).","journal-title":"Asian J. Androl."},{"key":"85169_CR20","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ng.2560","volume":"45","author":"RA Eeles","year":"2013","unstructured":"Eeles, R. A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385\u2013391. https:\/\/doi.org\/10.1038\/ng.2560 (2013).","journal-title":"Nat. Genet."},{"key":"85169_CR21","doi-asserted-by":"publisher","first-page":"D362","DOI":"10.1093\/nar\/gkw937","volume":"45","author":"D Szklarczyk","year":"2017","unstructured":"Szklarczyk, D. et al. The STRING database in 2017: Quality-controlled protein\u2013protein association networks, made broadly accessible. Nucleic Acids Res. 45, D362\u2013D368. https:\/\/doi.org\/10.1093\/nar\/gkw937 (2017).","journal-title":"Nucleic Acids Res."},{"key":"85169_CR22","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/bjc.2015.199","volume":"113","author":"J Sullivan","year":"2015","unstructured":"Sullivan, J. et al. An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality. Br. J. Cancer 113, 166\u2013172. https:\/\/doi.org\/10.1038\/bjc.2015.199 (2015).","journal-title":"Br. J. Cancer"},{"key":"85169_CR23","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1515\/hsz-2012-0211","volume":"393","author":"J Batra","year":"2012","unstructured":"Batra, J., O\u2019Mara, T., Patnala, R., Lose, F. & Clements, J. A. Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases. Biol. Chem. 393, 1365\u20131390. https:\/\/doi.org\/10.1515\/hsz-2012-0211 (2012).","journal-title":"Biol. Chem."},{"key":"85169_CR24","doi-asserted-by":"publisher","first-page":"5133","DOI":"10.1158\/1078-0432.CCR-14-0661","volume":"20","author":"Y He","year":"2014","unstructured":"He, Y. et al. The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients. Clin. Cancer Res. 20, 5133\u20135139. https:\/\/doi.org\/10.1158\/1078-0432.CCR-14-0661 (2014).","journal-title":"Clin. Cancer Res."},{"key":"85169_CR25","doi-asserted-by":"publisher","first-page":"2409","DOI":"10.1007\/s12253-020-00839-7","volume":"26","author":"N Kotarac","year":"2020","unstructured":"Kotarac, N., Dobrijevic, Z., Matijasevic, S., Savic-Pavicevic, D. & Brajuskovic, G. Association of KLK3, VAMP8 and MDM4 genetic variants within microRNA binding sites with prostate cancer: Evidence from Serbian population. Pathol. Oncol. Res. 26, 2409\u20132423. https:\/\/doi.org\/10.1007\/s12253-020-00839-7 (2020).","journal-title":"Pathol. Oncol. Res."},{"key":"85169_CR26","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1159\/000132629","volume":"48","author":"GR Sutherland","year":"1988","unstructured":"Sutherland, G. R. et al. Human prostate-specific antigen (APS) is a member of the glandular kallikrein gene family at 19q13. Cytogenet. Cell Genet. 48, 205\u2013207. https:\/\/doi.org\/10.1159\/000132629 (1988).","journal-title":"Cytogenet. Cell Genet."},{"key":"85169_CR27","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1210\/er.2009-0034","volume":"31","author":"MG Lawrence","year":"2010","unstructured":"Lawrence, M. G., Lai, J. & Clements, J. A. Kallikreins on steroids: Structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocr. Rev. 31, 407\u2013446. https:\/\/doi.org\/10.1210\/er.2009-0034 (2010).","journal-title":"Endocr. Rev."},{"key":"85169_CR28","doi-asserted-by":"publisher","first-page":"557","DOI":"10.18388\/abp.2005_3473","volume":"52","author":"I Katnik-Prastowska","year":"2005","unstructured":"Katnik-Prastowska, I., Przybysz, M. & Chelmonska-Soyta, A. Fibronectin fragments in human seminal plasma. Acta Biochim. Pol. 52, 557\u2013560 (2005).","journal-title":"Acta Biochim. Pol."},{"key":"85169_CR29","doi-asserted-by":"publisher","first-page":"10115","DOI":"10.1007\/s13277-015-4619-0","volume":"37","author":"K Xiao","year":"2016","unstructured":"Xiao, K. et al. Use of two gene panels for prostate cancer diagnosis and patient risk stratification. Tumour Biol. 37, 10115\u201310122. https:\/\/doi.org\/10.1007\/s13277-015-4619-0 (2016).","journal-title":"Tumour Biol."},{"key":"85169_CR30","doi-asserted-by":"publisher","first-page":"8386","DOI":"10.1158\/0008-5472.CAN-09-1504","volume":"69","author":"L Gan","year":"2009","unstructured":"Gan, L. et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res. 69, 8386\u20138394. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1504 (2009).","journal-title":"Cancer Res."},{"key":"85169_CR31","doi-asserted-by":"crossref","unstructured":"Das, D. K. & Ogunwobi, O. O. A novel microRNA-1207-3p\/FNDC1\/FN1\/AR regulatory pathway in prostate cancer. RNA Dis. 4 (2017).","DOI":"10.1017\/cts.2017.37"},{"key":"85169_CR32","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1158\/2159-8290.CD-14-1057","volume":"5","author":"S Stegeman","year":"2015","unstructured":"Stegeman, S. et al. A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer. Cancer Discov. 5, 368\u2013379. https:\/\/doi.org\/10.1158\/2159-8290.CD-14-1057 (2015).","journal-title":"Cancer Discov."},{"issue":"Suppl 1","key":"85169_CR33","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1186\/gb-2008-9-s1-s4","volume":"9","author":"S Mostafavi","year":"2008","unstructured":"Mostafavi, S., Ray, D., Warde-Farley, D., Grouios, C. & Morris, Q. GeneMANIA: A real-time multiple association network integration algorithm for predicting gene function. Genome Biol. 9(Suppl 1), S4. https:\/\/doi.org\/10.1186\/gb-2008-9-s1-s4 (2008).","journal-title":"Genome Biol."},{"key":"85169_CR34","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/pros.10256","volume":"56","author":"AH Fortier","year":"2003","unstructured":"Fortier, A. H. et al. Recombinant prostate specific antigen inhibits angiogenesis in vitro and in vivo. Prostate 56, 212\u2013219. https:\/\/doi.org\/10.1002\/pros.10256 (2003).","journal-title":"Prostate"},{"key":"85169_CR35","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1093\/carcin\/bgs150","volume":"33","author":"EK Amankwah","year":"2012","unstructured":"Amankwah, E. K., Sellers, T. A. & Park, J. Y. Gene variants in the angiogenesis pathway and prostate cancer. Carcinogenesis 33, 1259\u20131269. https:\/\/doi.org\/10.1093\/carcin\/bgs150 (2012).","journal-title":"Carcinogenesis"},{"key":"85169_CR36","doi-asserted-by":"publisher","first-page":"e0188842","DOI":"10.1371\/journal.pone.0188842","volume":"12","author":"D Jedroszka","year":"2017","unstructured":"Jedroszka, D., Orzechowska, M., Hamouz, R., Gorniak, K. & Bednarek, A. K. Markers of epithelial-to-mesenchymal transition reflect tumor biology according to patient age and Gleason score in prostate cancer. PLoS ONE 12, e0188842. https:\/\/doi.org\/10.1371\/journal.pone.0188842 (2017).","journal-title":"PLoS ONE"},{"key":"85169_CR37","doi-asserted-by":"publisher","first-page":"e0132028","DOI":"10.1371\/journal.pone.0132028","volume":"10","author":"A Giri","year":"2015","unstructured":"Giri, A., Edwards, T. L., Motley, S. S., Byerly, S. H. & Fowke, J. H. Genetic determinants of metabolism and benign prostate enlargement: Associations with prostate volume. PLoS ONE 10, e0132028. https:\/\/doi.org\/10.1371\/journal.pone.0132028 (2015).","journal-title":"PLoS ONE"},{"key":"85169_CR38","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1002\/gcc.20787","volume":"49","author":"AV Andreeva","year":"2010","unstructured":"Andreeva, A. V. & Kutuzov, M. A. Cadherin 13 in cancer. Genes Chromosomes Cancer 49, 775\u2013790. https:\/\/doi.org\/10.1002\/gcc.20787 (2010).","journal-title":"Genes Chromosomes Cancer"},{"key":"85169_CR39","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/bjc.2017.212","volume":"117","author":"Y Dai","year":"2017","unstructured":"Dai, Y. et al. The TGF-beta signalling negative regulator PICK1 represses prostate cancer metastasis to bone. Br. J. Cancer 117, 685\u2013694. https:\/\/doi.org\/10.1038\/bjc.2017.212 (2017).","journal-title":"Br. J. Cancer"},{"key":"85169_CR40","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1002\/pros.20526","volume":"67","author":"N Sharifi","year":"2007","unstructured":"Sharifi, N., Hurt, E. M., Kawasaki, B. T. & Farrar, W. L. TGFBR3 loss and consequences in prostate cancer. Prostate 67, 301\u2013311. https:\/\/doi.org\/10.1002\/pros.20526 (2007).","journal-title":"Prostate"},{"key":"85169_CR41","doi-asserted-by":"publisher","first-page":"892","DOI":"10.3389\/fgene.2020.00892","volume":"11","author":"YP Wu","year":"2020","unstructured":"Wu, Y. P. et al. Identification of prostate cancer-related circular RNA through bioinformatics analysis. Front. Genet. 11, 892. https:\/\/doi.org\/10.3389\/fgene.2020.00892 (2020).","journal-title":"Front. Genet."},{"key":"85169_CR42","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1093\/jnci\/91.19.1635","volume":"91","author":"AH Fortier","year":"1999","unstructured":"Fortier, A. H., Nelson, B. J., Grella, D. K. & Holaday, J. W. Antiangiogenic activity of prostate-specific antigen. J. Natl. Cancer Inst. 91, 1635\u20131640 (1999).","journal-title":"J. Natl. Cancer Inst."},{"key":"85169_CR43","doi-asserted-by":"publisher","first-page":"22485","DOI":"10.1074\/jbc.M115.658104","volume":"290","author":"SA Baker","year":"2015","unstructured":"Baker, S. A., Lombardi, L. M. & Zoghbi, H. Y. Karyopherin alpha 3 and karyopherin alpha 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. J. Biol. Chem. 290, 22485\u201322493. https:\/\/doi.org\/10.1074\/jbc.M115.658104 (2015).","journal-title":"J. Biol. Chem."},{"key":"85169_CR44","doi-asserted-by":"publisher","first-page":"e1005803","DOI":"10.1371\/journal.ppat.1005803","volume":"12","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. The prostaglandin E2-EP3 receptor axis regulates anaplasma phagocytophilum-mediated NLRC4 inflammasome activation. PLoS Pathog. 12, e1005803. https:\/\/doi.org\/10.1371\/journal.ppat.1005803 (2016).","journal-title":"PLoS Pathog."},{"key":"85169_CR45","doi-asserted-by":"publisher","first-page":"11827","DOI":"10.26355\/eurrev_202011_23840","volume":"24","author":"MK Sundaram","year":"2020","unstructured":"Sundaram, M. K. et al. Phytochemicals induce apoptosis by modulation of nitric oxide signaling pathway in cervical cancer cells. Eur. Rev. Med. Pharmacol. Sci. 24, 11827\u201311844. https:\/\/doi.org\/10.26355\/eurrev_202011_23840 (2020).","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"85169_CR46","doi-asserted-by":"publisher","first-page":"2999","DOI":"10.1158\/0008-5472.CAN-13-2740","volume":"74","author":"M Augsten","year":"2014","unstructured":"Augsten, M. et al. Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res. 74, 2999\u20133010. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-2740 (2014).","journal-title":"Cancer Res."},{"key":"85169_CR47","doi-asserted-by":"publisher","first-page":"3772","DOI":"10.3892\/ol.2018.7785","volume":"15","author":"M Ota","year":"2018","unstructured":"Ota, M. et al. Association between receptor interacting serine\/threonine kinase 2 polymorphisms and gastric cancer susceptibility. Oncol. Lett. 15, 3772\u20133778. https:\/\/doi.org\/10.3892\/ol.2018.7785 (2018).","journal-title":"Oncol. Lett."},{"key":"85169_CR48","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nature18003","volume":"534","author":"P Mertins","year":"2016","unstructured":"Mertins, P. et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534, 55\u201362. https:\/\/doi.org\/10.1038\/nature18003 (2016).","journal-title":"Nature"},{"key":"85169_CR49","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1158\/1055-9965.EPI-11-0264","volume":"20","author":"KM Reid-Lombardo","year":"2011","unstructured":"Reid-Lombardo, K. M. et al. Inflammation-related gene variants as risk factors for pancreatic cancer. Cancer Epidemiol. Biomark. Prev. 20, 1251\u20131254. https:\/\/doi.org\/10.1158\/1055-9965.EPI-11-0264 (2011).","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"85169_CR50","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/s11060-013-1122-6","volume":"113","author":"DM Backes","year":"2013","unstructured":"Backes, D. M. et al. Single-nucleotide polymorphisms of allergy-related genes and risk of adult glioma. J. Neurooncol. 113, 229\u2013238. https:\/\/doi.org\/10.1007\/s11060-013-1122-6 (2013).","journal-title":"J. Neurooncol."},{"key":"85169_CR51","doi-asserted-by":"publisher","first-page":"2618","DOI":"10.1016\/j.ejca.2011.05.011","volume":"47","author":"M Ibarrola-Villava","year":"2011","unstructured":"Ibarrola-Villava, M. et al. Genetic polymorphisms in DNA repair and oxidative stress pathways associated with malignant melanoma susceptibility. Eur. J. Cancer 47, 2618\u20132625. https:\/\/doi.org\/10.1016\/j.ejca.2011.05.011 (2011).","journal-title":"Eur. J. Cancer"},{"key":"85169_CR52","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.18632\/oncotarget.1300","volume":"4","author":"ZD Nassar","year":"2013","unstructured":"Nassar, Z. D. et al. PTRF\/Cavin-1 decreases prostate cancer angiogenesis and lymphangiogenesis. Oncotarget 4, 1844\u20131855. https:\/\/doi.org\/10.18632\/oncotarget.1300 (2013).","journal-title":"Oncotarget"},{"key":"85169_CR53","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1158\/1055-9965.EPI-06-0767","volume":"16","author":"JM Cunningham","year":"2007","unstructured":"Cunningham, J. M. et al. Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol. Biomark. Prev. 16, 969\u2013978. https:\/\/doi.org\/10.1158\/1055-9965.EPI-06-0767 (2007).","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"85169_CR54","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.juro.2012.06.030","volume":"188","author":"CF Zambon","year":"2012","unstructured":"Zambon, C. F. et al. Effectiveness of the combined evaluation of KLK3 genetics and free-to-total prostate specific antigen ratio for prostate cancer diagnosis. J. Urol. 188, 1124\u20131130. https:\/\/doi.org\/10.1016\/j.juro.2012.06.030 (2012).","journal-title":"J. Urol."},{"key":"85169_CR55","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1136\/jcp.2007.050906","volume":"61","author":"K Wako","year":"2008","unstructured":"Wako, K. et al. Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate cancer. J. Clin. Pathol. 61, 448\u2013454. https:\/\/doi.org\/10.1136\/jcp.2007.050906 (2008).","journal-title":"J. Clin. Pathol."},{"key":"85169_CR56","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12894-020-00627-0","volume":"20","author":"A Hamid","year":"2020","unstructured":"Hamid, A. et al. Early upregulation of AR and steroidogenesis enzyme expression after 3 months of androgen-deprivation therapy. BMC Urol. 20, 71. https:\/\/doi.org\/10.1186\/s12894-020-00627-0 (2020).","journal-title":"BMC Urol."},{"key":"85169_CR57","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1023\/a:1006723011835","volume":"17","author":"B Davidson","year":"1999","unstructured":"Davidson, B. et al. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin. Exp. Metastasis 17, 799\u2013808. https:\/\/doi.org\/10.1023\/a:1006723011835 (1999).","journal-title":"Clin. Exp. Metastasis"},{"key":"85169_CR58","doi-asserted-by":"publisher","first-page":"D146","DOI":"10.1093\/nar\/gku1104","volume":"43","author":"N Wong","year":"2015","unstructured":"Wong, N. & Wang, X. miRDB: An online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 43, D146-152. https:\/\/doi.org\/10.1093\/nar\/gku1104 (2015).","journal-title":"Nucleic Acids Res."},{"key":"85169_CR59","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.prp.2005.07.003","volume":"201","author":"G Aslan","year":"2005","unstructured":"Aslan, G. et al. Vascular endothelial growth factor expression in untreated and androgen-deprived patients with prostate cancer. Pathol. Res. Pract. 201, 593\u2013598. https:\/\/doi.org\/10.1016\/j.prp.2005.07.003 (2005).","journal-title":"Pathol. Res. Pract."},{"key":"85169_CR60","doi-asserted-by":"publisher","first-page":"5251","DOI":"10.1038\/onc.2013.463","volume":"33","author":"JB Tennakoon","year":"2014","unstructured":"Tennakoon, J. B. et al. Androgens regulate prostate cancer cell growth via an AMPK-PGC-1alpha-mediated metabolic switch. Oncogene 33, 5251\u20135261. https:\/\/doi.org\/10.1038\/onc.2013.463 (2014).","journal-title":"Oncogene"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85169-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85169-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85169-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T07:38:44Z","timestamp":1670053124000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85169-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["85169"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-85169-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,4,29]]},"assertion":[{"value":"27 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 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":"9264"}}