{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T23:21:13Z","timestamp":1774394473196,"version":"3.50.1"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"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>Equine penile squamous cell carcinoma (EpSCC) is a relatively common cutaneous neoplasm with a poor prognosis. In this study, we aimed to determine the protein expression and colocalisation of FRA1, c-Myc, Cyclin D1, and MMP7 in normal (NT), tumour (T), hyperplastic epidermis and\/or squamous papilloma (Hyp\/Pap), poorly-differentiated (PDSCC), or well-differentiated (WDSCC) EpSCC using a tissue array approach. Further objectives were to correlate protein expression to (i) levels of inflammation, using a convolutional neural network (ii) equine papillomavirus 2 (EcPV2) infection, detected using PCR amplification. We found an increase in expression of FRA1 in EpSCC compared to NT samples. c-Myc expression was higher in Hyp\/Pap and WDSCC but not PDSCC whereas MMP7 was reduced in WDSCC compared with NT. There was a significant increase in the global intersection coefficient (GIC) of FRA1 with MMP7, c-Myc, and Cyclin D1 in EpSCC. Conversely, GIC for MMP7 with c-Myc was reduced in EpSCC tissue. Inflammation was positively associated with EcPV2 infection in both NT and EpSCC but not Hyp\/Pap. Changes in protein expression could be correlated with EcPV2 for Cyclin D1 and c-Myc. Our results evaluate novel biomarkers of EpSCC and a putative correlation between the expression of biomarkers, EcPV2 infection and inflammation.<\/jats:p>","DOI":"10.1038\/s41598-020-64014-3","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T10:05:02Z","timestamp":1589277902000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Equine penile squamous cell carcinoma: expression of biomarker proteins and EcPV2"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8508-3754","authenticated-orcid":false,"given":"Callum","family":"Arthurs","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0296-5896","authenticated-orcid":false,"given":"Alejandro","family":"Suarez-Bonnet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Willis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boyu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Machulla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim S.","family":"Mair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Millar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Thrasivoulou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6027-1879","authenticated-orcid":false,"given":"Simon L.","family":"Priestnall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aamir","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,12]]},"reference":[{"key":"64014_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1177\/104063870601800121","volume":"18","author":"BA Valentine","year":"2006","unstructured":"Valentine, B. A. Survey of equine cutaneous neoplasia in the Pacific Northwest. J Vet Diagn Invest 18, 123\u2013126, https:\/\/doi.org\/10.1177\/104063870601800121 (2006).","journal-title":"J Vet Diagn Invest"},{"key":"64014_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.vetmic.2012.02.005","volume":"158","author":"L Bogaert","year":"2012","unstructured":"Bogaert, L. et al. EcPV2 DNA in equine genital squamous cell carcinomas and normal genital mucosa. Vet Microbiol 158, 33\u201341, https:\/\/doi.org\/10.1016\/j.vetmic.2012.02.005 (2012).","journal-title":"Vet Microbiol"},{"key":"64014_CR3","doi-asserted-by":"crossref","unstructured":"Scott, D. & Miller, W. Neoplasms, cysts, hamartomas and keratoses. Equine dermatology, 468-516 (2011).","DOI":"10.1016\/B978-1-4377-0920-9.00016-0"},{"key":"64014_CR4","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1111\/j.2042-3306.2010.00290.x","volume":"42","author":"JGB van den Top","year":"2010","unstructured":"van den Top, J. G. B. et al. Penile and preputial tumours in the horse: Literature review and proposal of a standardised approach. Equine Veterinary Journal 42, 746\u2013757, https:\/\/doi.org\/10.1111\/j.2042-3306.2010.00290.x (2010).","journal-title":"Equine Veterinary Journal"},{"key":"64014_CR5","unstructured":"Theilen, G. H. & Madewell, B. R. Veterinary cancer medicine. (Lea & Febiger Philadelphia, 1987)."},{"key":"64014_CR6","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1111\/evj.12421","volume":"48","author":"EJ Knowles","year":"2016","unstructured":"Knowles, E. J., Tremaine, W. H., Pearson, G. R. & Mair, T. S. A database survey of equine tumours in the United Kingdom. Equine Vet J 48, 280\u2013284, https:\/\/doi.org\/10.1111\/evj.12421 (2016).","journal-title":"Equine Vet J"},{"key":"64014_CR7","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1177\/0300985815583095","volume":"52","author":"KW Zhu","year":"2015","unstructured":"Zhu, K. W., Affolter, V. K., Gaynor, A. M., Dela Cruz, F. N. & Pesavento, P. A. Equine Genital Squamous Cell Carcinoma: In Situ Hybridization Identifies a Distinct Subset Containing Equus caballus Papillomavirus 2. Vet Pathol 52, 1067\u20131072, https:\/\/doi.org\/10.1177\/0300985815583095 (2015).","journal-title":"Vet Pathol"},{"key":"64014_CR8","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.ccr.2005.04.014","volume":"7","author":"KE De Visser","year":"2005","unstructured":"De Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer cell 7, 411\u2013423 (2005).","journal-title":"Cancer cell"},{"key":"64014_CR9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.gde.2009.11.004","volume":"20","author":"SI Grivennikov","year":"2010","unstructured":"Grivennikov, S. I. & Karin, M. Inflammation and oncogenesis: a vicious connection. Current opinion in genetics & development 20, 65\u201371 (2010).","journal-title":"Current opinion in genetics & development"},{"key":"64014_CR10","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1073\/pnas.80.12.3812","volume":"80","author":"M D\u00fcrst","year":"1983","unstructured":"D\u00fcrst, M., Gissmann, L., Ikenberg, H. & Zur Hausen, H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proceedings of the National Academy of Sciences 80, 3812\u20133815 (1983).","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"64014_CR11","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1016\/j.jadohealth.2010.01.016","volume":"46","author":"AK Chaturvedi","year":"2010","unstructured":"Chaturvedi, A. K. Beyond cervical cancer: burden of other HPV-related cancers among men and women. J Adolesc Health 46, S20\u201326, https:\/\/doi.org\/10.1016\/j.jadohealth.2010.01.016 (2010).","journal-title":"J Adolesc Health"},{"key":"64014_CR12","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2746\/095777309X390272","volume":"21","author":"Y Elce","year":"2009","unstructured":"Elce, Y. The aetiopathogenesis of squamous cell carcinomas in horses. Where are we? Equine Veterinary Education 21, 17\u201318 (2009).","journal-title":"Equine Veterinary Education"},{"key":"64014_CR13","doi-asserted-by":"crossref","unstructured":"Walboomers, J. M. M. et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189, 12\u201319, 10.1002\/(Sici)1096-9896(199909)189:1<12::Aid-Path431>3.0.Co;2-F (1999).","DOI":"10.1002\/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F"},{"key":"64014_CR14","first-page":"28","volume":"71","author":"RC Postey","year":"2007","unstructured":"Postey, R. C., Appleyard, G. D. & Kidney, B. A. Evaluation of equine papillomas, aural plaques, and sarcoids for the presence of Equine papillomavirus DNA and Papillomavirus antigen. Can J Vet Res 71, 28\u201333 (2007).","journal-title":"Can J Vet Res"},{"key":"64014_CR15","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1177\/0300985810396516","volume":"48","author":"CG Knight","year":"2011","unstructured":"Knight, C. G., Munday, J. S., Peters, J. & Dunowska, M. Equine Penile Squamous Cell Carcinomas Are Associated With the Presence of Equine Papillomavirus Type 2 DNA Sequences. Vet Pathol 48, 1190\u20131194, https:\/\/doi.org\/10.1177\/0300985810396516 (2011).","journal-title":"Vet Pathol"},{"key":"64014_CR16","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1177\/0300985812463403","volume":"50","author":"CE Lange","year":"2013","unstructured":"Lange, C. E. et al. EcPV2 DNA in equine papillomas and in situ and invasive squamous cell carcinomas supports papillomavirus etiology. Vet Pathol 50, 686\u2013692, https:\/\/doi.org\/10.1177\/0300985812463403 (2013).","journal-title":"Vet Pathol"},{"key":"64014_CR17","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.virol.2010.02.002","volume":"401","author":"HU Bernard","year":"2010","unstructured":"Bernard, H. U. et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 401, 70\u201379, https:\/\/doi.org\/10.1016\/j.virol.2010.02.002 (2010).","journal-title":"Virology"},{"key":"64014_CR18","doi-asserted-by":"publisher","first-page":"e0124395","DOI":"10.1371\/journal.pone.0124395","volume":"10","author":"M Arya","year":"2015","unstructured":"Arya, M. et al. Targets of wnt\/\u00df-catenin transcription in penile carcinoma. PLoS. One 10, e0124395, https:\/\/doi.org\/10.1371\/journal.pone.0124395 (2015).","journal-title":"PLoS. One"},{"key":"64014_CR19","doi-asserted-by":"publisher","first-page":"22429","DOI":"10.1074\/jbc.R600015200","volume":"281","author":"MD Gordon","year":"2006","unstructured":"Gordon, M. D. & Nusse, R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281, 22429\u201322433 (2006).","journal-title":"J Biol Chem"},{"key":"64014_CR20","doi-asserted-by":"publisher","first-page":"C511","DOI":"10.1152\/ajpcell.00117.2015","volume":"309","author":"L Novellasdemunt","year":"2015","unstructured":"Novellasdemunt, L., Antas, P. & Li, V. S. Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms. Am J Physiol Cell Physiol 309, C511\u2013521, https:\/\/doi.org\/10.1152\/ajpcell.00117.2015 (2015).","journal-title":"Am J Physiol Cell Physiol"},{"key":"64014_CR21","doi-asserted-by":"crossref","unstructured":"Moparthi, L. & Koch, S. Wnt signaling in intestinal inflammation. Differentiation (2019).","DOI":"10.1016\/j.diff.2019.01.002"},{"key":"64014_CR22","doi-asserted-by":"publisher","first-page":"3748","DOI":"10.1128\/MCB.15.7.3748","volume":"15","author":"G Bergers","year":"1995","unstructured":"Bergers, G., Graninger, P., Braselmann, S., Wrighton, C. & Busslinger, M. Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. Mol Cell Biol 15, 3748\u20133758 (1995).","journal-title":"Mol Cell Biol"},{"key":"64014_CR23","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/ar2338","volume":"10","author":"R Zenz","year":"2008","unstructured":"Zenz, R. et al. Activator protein 1 (Fos\/Jun) functions in inflammatory bone and skin disease. Arthritis research & therapy 10, 201 (2008).","journal-title":"Arthritis research & therapy"},{"key":"64014_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.gene.2006.05.001","volume":"379","author":"MR Young","year":"2006","unstructured":"Young, M. R. & Colburn, N. H. Fra-1 a target for cancer prevention or intervention. Gene 379, 1\u201311 (2006).","journal-title":"Gene"},{"key":"64014_CR25","doi-asserted-by":"publisher","first-page":"9827","DOI":"10.1073\/pnas.96.17.9827","volume":"96","author":"MR Young","year":"1999","unstructured":"Young, M. R. et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 96, 9827\u20139832 (1999).","journal-title":"Proc Natl Acad Sci USA"},{"key":"64014_CR26","doi-asserted-by":"publisher","first-page":"19","DOI":"10.4161\/cbt.10.1.11944","volume":"10","author":"D Zhang","year":"2010","unstructured":"Zhang, D., Ma, Q. Y., Hu, H. T. & Zhang, M. beta(2)-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF kappa B and AP-1. Cancer Biol Ther 10, 19\u201329, https:\/\/doi.org\/10.4161\/cbt.10.1.11944 (2010).","journal-title":"Cancer Biol Ther"},{"key":"64014_CR27","first-page":"177","volume":"22","author":"S Hein","year":"2009","unstructured":"Hein, S. et al. Expression of Jun and Fos proteins in ovarian tumors of different malignant potential and in ovarian cancer cell lines. Oncol Rep 22, 177\u2013183 (2009).","journal-title":"Oncol Rep"},{"key":"64014_CR28","doi-asserted-by":"publisher","first-page":"e84295","DOI":"10.1371\/journal.pone.0084295","volume":"8","author":"AJ Symes","year":"2013","unstructured":"Symes, A. J. et al. Quantitative Analysis of BTF3, HINT1, NDRG1 and ODC1 Protein Over-Expression in Human Prostate Cancer Tissue. PLoS. One 8, e84295, https:\/\/doi.org\/10.1371\/journal.pone.0084295 (2013).","journal-title":"PLoS. One"},{"key":"64014_CR29","doi-asserted-by":"publisher","first-page":"e0161103","DOI":"10.1371\/journal.pone.0161103","volume":"11","author":"A Giuliano","year":"2016","unstructured":"Giuliano, A. et al. Quantitative Expression and Co-Localization of Wnt Signalling Related Proteins in Feline Squamous Cell Carcinoma. PLoS One 11, e0161103, https:\/\/doi.org\/10.1371\/journal.pone.0161103 (2016).","journal-title":"PLoS One"},{"key":"64014_CR30","doi-asserted-by":"publisher","first-page":"e0186047","DOI":"10.1371\/journal.pone.0186047","volume":"12","author":"C Arthurs","year":"2017","unstructured":"Arthurs, C. et al. Expression of ribosomal proteins in normal and cancerous human prostate tissue. PLoS One 12, e0186047, https:\/\/doi.org\/10.1371\/journal.pone.0186047 (2017).","journal-title":"PLoS One"},{"key":"64014_CR31","doi-asserted-by":"publisher","unstructured":"Cao, K. et al. Quantitative Analysis of Seven New Prostate Cancer Biomarkers and the Potential Future of the \u2018Biomarker Laboratory\u2019. Diagnostics (Basel) 8, https:\/\/doi.org\/10.3390\/diagnostics8030049 (2018).","DOI":"10.3390\/diagnostics8030049"},{"key":"64014_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emm.2006.1","volume":"38","author":"A Kikuchi","year":"2006","unstructured":"Kikuchi, A., Kishida, S. & Yamamoto, H. Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. Experimental & molecular medicine 38, 1 (2006).","journal-title":"Experimental & molecular medicine"},{"key":"64014_CR33","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1074\/jbc.M309999200","volume":"279","author":"JF Gera","year":"2004","unstructured":"Gera, J. F. et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 279, 2737\u20132746 (2004).","journal-title":"J Biol Chem"},{"key":"64014_CR34","doi-asserted-by":"publisher","first-page":"8571","DOI":"10.1038\/sj.onc.1207902","volume":"23","author":"T Asano","year":"2004","unstructured":"Asano, T. et al. The PI 3-kinase\/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-\u03baB and c-Myc in pancreatic cancer cells. Oncogene 23, 8571 (2004).","journal-title":"Oncogene"},{"key":"64014_CR35","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.3892\/ol.2015.3436","volume":"10","author":"G Shan","year":"2015","unstructured":"Shan, G. & Tang, T. Expression of cyclin D1 and cyclin E in urothelial bladder carcinoma detected in tissue chips using a quantum dot immunofluorescence technique. Oncology letters 10, 1271\u20131276 (2015).","journal-title":"Oncology letters"},{"key":"64014_CR36","first-page":"21222","volume":"8","author":"S Xu","year":"2015","unstructured":"Xu, S. et al. The expression of AEG-1 and Cyclin D1 in human bladder urothelial carcinoma and their clinicopathological significance. International journal of clinical and experimental medicine 8, 21222 (2015).","journal-title":"International journal of clinical and experimental medicine"},{"key":"64014_CR37","doi-asserted-by":"publisher","first-page":"67","DOI":"10.3233\/BLC-170124","volume":"4","author":"C Bolenz","year":"2018","unstructured":"Bolenz, C. et al. Decreased Invasion of Urothelial Carcinoma of the Bladder by Inhibition of Matrix-Metalloproteinase 7. Bladder Cancer 4, 67\u201375 (2018).","journal-title":"Bladder Cancer"},{"key":"64014_CR38","doi-asserted-by":"publisher","first-page":"e2691","DOI":"10.1038\/cddis.2017.118","volume":"8","author":"J Liu","year":"2017","unstructured":"Liu, J. et al. Solute carrier family 12 member 5 promotes tumor invasion\/metastasis of bladder urothelial carcinoma by enhancing NF-\u03baB\/MMP-7 signaling pathway. Cell death & disease 8, e2691 (2017).","journal-title":"Cell death & disease"},{"key":"64014_CR39","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1089\/gtmb.2015.0123","volume":"19","author":"L Tao","year":"2015","unstructured":"Tao, L. et al. MMP1, 2, 3, 7, and 9 gene polymorphisms and urinary cancer risk: a meta-analysis. Genetic testing and molecular biomarkers 19, 548\u2013555 (2015).","journal-title":"Genetic testing and molecular biomarkers"},{"key":"64014_CR40","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s00441-013-1715-6","volume":"354","author":"Y Li","year":"2013","unstructured":"Li, Y. et al. The Lin28\/let-7a\/c-Myc pathway plays a role in non-muscle invasive bladder cancer. Cell and tissue research 354, 533\u2013541 (2013).","journal-title":"Cell and tissue research"},{"key":"64014_CR41","doi-asserted-by":"publisher","first-page":"e0127908","DOI":"10.1371\/journal.pone.0127908","volume":"10","author":"F Massari","year":"2015","unstructured":"Massari, F. et al. Prognostic value of beta-tubulin-3 and c-Myc in muscle invasive urothelial carcinoma of the bladder. PloS one 10, e0127908 (2015).","journal-title":"PloS one"},{"key":"64014_CR42","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.juro.2013.07.019","volume":"191","author":"K-C Jeong","year":"2014","unstructured":"Jeong, K.-C. et al. Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth. The Journal of urology 191, 510\u2013518 (2014).","journal-title":"The Journal of urology"},{"key":"64014_CR43","doi-asserted-by":"publisher","unstructured":"Zhang, L., Liu, H. J., Mu, X. D., Cui, J. L. & Peng, Z. G. Dysregulation of Fra1 expression by Wnt\/beta-catenin signalling promotes glioma aggressiveness through epithelial-mesenchymal transition. Bioscience Rep 37, Artn Bsr20160643, https:\/\/doi.org\/10.1042\/Bsr20160643 (2017).","DOI":"10.1042\/Bsr20160643"},{"key":"64014_CR44","doi-asserted-by":"publisher","unstructured":"Kim, J. H., Park, S. Y., Jun, Y., Kim, J. Y. & Nam, J. S. Roles of Wnt Target Genes in the Journey of Cancer Stem Cells. International Journal of Molecular Sciences 18, ARTN 1604, https:\/\/doi.org\/10.3390\/ijms18081604 (2017).","DOI":"10.3390\/ijms18081604"},{"key":"64014_CR45","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/nri2586","volume":"9","author":"SL Gaffen","year":"2009","unstructured":"Gaffen, S. L. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9, 556\u2013567, https:\/\/doi.org\/10.1038\/nri2586 (2009).","journal-title":"Nat Rev Immunol"},{"key":"64014_CR46","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3892\/or.2015.4395","volume":"35","author":"GW Zhong","year":"2016","unstructured":"Zhong, G. W. et al. Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway. Oncol Rep 35, 447\u2013453, https:\/\/doi.org\/10.3892\/or.2015.4395 (2016).","journal-title":"Oncol Rep"},{"key":"64014_CR47","doi-asserted-by":"publisher","unstructured":"Motrich, R. D., Castro, G. M. & Caputto, B. L. Old Players with a Newly Defined Function: Fra-1 and c-Fos Support Growth of Human Malignant Breast Tumors by Activating Membrane Biogenesis at the Cytoplasm. Plos One 8, ARTN e53211 https:\/\/doi.org\/10.1371\/journal.pone.0053211 (2013).","DOI":"10.1371\/journal.pone.0053211"},{"key":"64014_CR48","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1038\/onc.2011.336","volume":"31","author":"AE Sayan","year":"2012","unstructured":"Sayan, A. E. et al. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 31, 1493\u20131503, https:\/\/doi.org\/10.1038\/onc.2011.336 (2012).","journal-title":"Oncogene"},{"key":"64014_CR49","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1002\/hep.24175","volume":"53","author":"T Kireva","year":"2011","unstructured":"Kireva, T. et al. Transcription Factor Fra-1 Induces Cholangitis and Liver Fibrosis. Hepatology 53, 1259\u20131269, https:\/\/doi.org\/10.1002\/hep.24175 (2011).","journal-title":"Hepatology"},{"key":"64014_CR50","doi-asserted-by":"publisher","unstructured":"Gao, D., Chen, H. Q. & Yang, Y. M. Specific knockdown of HOXB7 inhibits cutaneous squamous cell carcinoma cell migration and invasion while inducing apoptosis via Wnt\/beta-catenin signaling pathway. Am J Physiol Cell Physiol, https:\/\/doi.org\/10.1152\/ajpcell.00291.2017 (2018).","DOI":"10.1152\/ajpcell.00291.2017"},{"key":"64014_CR51","doi-asserted-by":"publisher","unstructured":"Chen, Y. P. et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol, https:\/\/doi.org\/10.1093\/annonc\/mdy470 (2018).","DOI":"10.1093\/annonc\/mdy470"},{"key":"64014_CR52","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s00345-008-0302-z","volume":"27","author":"M Bleeker","year":"2009","unstructured":"Bleeker, M. et al. Penile cancer: epidemiology, pathogenesis and prevention. World journal of urology 27, 141 (2009).","journal-title":"World journal of urology"},{"key":"64014_CR53","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/S0140-6736(00)04046-0","volume":"357","author":"F Balkwill","year":"2001","unstructured":"Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? The lancet 357, 539\u2013545 (2001).","journal-title":"The lancet"},{"key":"64014_CR54","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1056\/NEJM198612253152606","volume":"315","author":"HF Dvorak","year":"1986","unstructured":"Dvorak, H. F. Tumors: wounds that do not heal. New England Journal of Medicine 315, 1650\u20131659 (1986).","journal-title":"New England Journal of Medicine"},{"key":"64014_CR55","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1084\/jem.71.4.469","volume":"71","author":"JG Kidd","year":"1940","unstructured":"Kidd, J. G. & Rous, P. Cancers deriving from the virus papillomas of wild rabbits under natural conditions. Journal of Experimental Medicine 71, 469\u2013494 (1940).","journal-title":"Journal of Experimental Medicine"},{"key":"64014_CR56","doi-asserted-by":"publisher","first-page":"e1242","DOI":"10.1016\/S1569-9056(17)30771-6","volume":"16","author":"S H\u00f6lters","year":"2017","unstructured":"H\u00f6lters, S. et al. Histopathologic and prognostic correlations regarding human papillomavirus (HPV) infection in penile squamous cell carcinomas (SCC) considering the novel 2016 WHO classification. European Urology Supplements 16, e1242 (2017).","journal-title":"European Urology Supplements"},{"key":"64014_CR57","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1177\/1040638713511618","volume":"26","author":"KM Newkirk","year":"2014","unstructured":"Newkirk, K. M. et al. Detection of papillomavirus in equine periocular and penile squamous cell carcinoma. J Vet Diagn Invest 26, 131\u2013135, https:\/\/doi.org\/10.1177\/1040638713511618 (2014).","journal-title":"J Vet Diagn Invest"},{"key":"64014_CR58","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706","volume":"27","author":"JE Smith-Garvin","year":"2009","unstructured":"Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annual review of immunology 27, 591\u2013619 (2009).","journal-title":"Annual review of immunology"},{"key":"64014_CR59","first-page":"608","volume":"36","author":"AD D\u2019Angeac","year":"1993","unstructured":"D\u2019Angeac, A. D. et al. Increased percentage of CD3. CD57+ lymphocytes in patients with rheumatoid arthritis. Correlation with duration of disease. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 36, 608\u2013612 (1993).","journal-title":"CD57+ lymphocytes in patients with rheumatoid arthritis. Correlation with duration of disease. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology"},{"key":"64014_CR60","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0008-6363(03)00362-6","volume":"60","author":"A Yndestad","year":"2003","unstructured":"Yndestad, A. et al. Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovascular research 60, 141\u2013146 (2003).","journal-title":"Cardiovascular research"},{"key":"64014_CR61","first-page":"548","volume":"82","author":"M Blanchard-Channell","year":"1994","unstructured":"Blanchard-Channell, M., Moore, P. F. & Stott, J. L. Characterization of monoclonal antibodies specific for equine homologues of CD3 and CD5. Immunology 82, 548 (1994).","journal-title":"Immunology"},{"key":"64014_CR62","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9, 671\u2013675 (2012).","journal-title":"Nat Methods"},{"key":"64014_CR63","unstructured":"Chollet, F. et al. Keras. https:\/\/github.com\/keras-team\/keras (2015)."},{"key":"64014_CR64","unstructured":"Abadi, M. et al. Tensorflow: Large-scale machine learning on heterogeneous distributed systems. arXiv preprint arXiv:1603.04467 (2016)."},{"key":"64014_CR65","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.csbj.2018.01.001","volume":"16","author":"D Komura","year":"2018","unstructured":"Komura, D. & Ishikawa, S. Machine learning methods for histopathological image analysis. Computational and structural biotechnology journal 16, 34\u201342 (2018).","journal-title":"Computational and structural biotechnology journal"},{"key":"64014_CR66","doi-asserted-by":"publisher","first-page":"696","DOI":"10.2460\/javma.243.5.696","volume":"243","author":"AJ Fulton","year":"2013","unstructured":"Fulton, A. J., Nemec, A., Murphy, B. G., Kass, P. H. & Verstraete, F. J. Risk factors associated with survival in dogs with nontonsillar oral squamous cell carcinoma 31 cases (1990\u20132010). Journal of the American Veterinary Medical Association 243, 696\u2013702 (2013).","journal-title":"Journal of the American Veterinary Medical Association"},{"key":"64014_CR67","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1146\/annurev-immunol-042617-053429","volume":"36","author":"A Alcover","year":"2018","unstructured":"Alcover, A., Alarc\u00f3n, B. & Di Bartolo, V. Cell biology of T cell receptor expression and regulation. Annual review of immunology 36, 103\u2013125 (2018).","journal-title":"Annual review of immunology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64014-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64014-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64014-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T10:00:13Z","timestamp":1670320813000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64014-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,12]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["64014"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-64014-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,12]]},"assertion":[{"value":"6 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2020","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":"7863"}}