{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:11:18Z","timestamp":1740147078256,"version":"3.37.3"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673797"],"award-info":[{"award-number":["81673797"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Backgrounds<\/jats:title>\n<jats:p><jats:italic>KLKs<\/jats:italic> have been proved to be key regulators of the tumor microenvironment. In this study, we explored the potential of <jats:italic>Kallikrein-related peptidases<\/jats:italic> (<jats:italic>KLKs<\/jats:italic>) as clinical diagnostic and prognostic markers in patients with kidney renal clear cell carcinoma (KIRC) as well as their relationship with common immuno-inhibitor and immune cell infiltration in the tumor microenvironment to provide new targets and novel ideas for KIRC therapy.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UCSC Xena, Genotype-Tissue Expression (GTEx), Kaplan-Meier plotter, cBioPortal, STRING, GeneMANIA, and TISIDB were used to analyze the differential expression, prognostic value, gene changes, molecular interaction, and immune infiltration of <jats:italic>KLKs<\/jats:italic> in patients with KIRC.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>From the gene expression level, it can be determined that <jats:italic>KLK1<\/jats:italic>, <jats:italic>KLK6<\/jats:italic>, and <jats:italic>KLK7<\/jats:italic> are differentially expressed in KIRC and normal tissues. From the perspective of clinical prognosis, <jats:italic>KLK1<\/jats:italic>, <jats:italic>KLK13<\/jats:italic>, and <jats:italic>KLK14<\/jats:italic> are highly correlated with the clinical prognosis of KIRC. The expression of <jats:italic>KLKs<\/jats:italic> is regulated by various immunosuppressive agents, with KDR, PVRL2, and VTCN1 being the most significant. The expression of <jats:italic>KLKs<\/jats:italic> is significantly correlated with the infiltration of various immune cells, of which Eosinophils and Neutrophils are the most significant.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p><jats:italic>KLK1<\/jats:italic>, <jats:italic>KLK6<\/jats:italic>, <jats:italic>KLK7<\/jats:italic>, <jats:italic>KLK13<\/jats:italic>, and <jats:italic>KLK14<\/jats:italic> have potential as diagnostic and prognostic biomarkers, among which <jats:italic>KLK1<\/jats:italic> is the most significant. This study may provide detailed immune information and promising targets for KIRC immunotherapy to assist in designing new immunotherapies.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0305070","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T17:37:23Z","timestamp":1723138643000},"page":"e0305070","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["An integrated bioinformatic investigation of kallikrein gene family members in kidney renel cell carcinoma"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2177-5708","authenticated-orcid":true,"given":"Baoquan","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyun","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengzhen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5608-7964","authenticated-orcid":true,"given":"Peitong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"issue":"21\u201322","key":"pone.0305070.ref001","doi-asserted-by":"crossref","first-page":"6735","DOI":"10.1007\/s00018-021-03922-7","article-title":"Kallikreins emerge as new regulators of viral infections","volume":"78","author":"G Pampalakis","year":"2021","journal-title":"Cell Mol Life Sci"},{"issue":"2","key":"pone.0305070.ref002","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jdermsci.2019.06.007","article-title":"Physiological and pathological roles of kallikrein-related peptidases in the epidermis","volume":"95","author":"M. Kishibe","year":"2019","journal-title":"J Dermatol Sci"},{"issue":"4","key":"pone.0305070.ref003","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41568-021-00436-z","article-title":"Remodelling of the tumour microenvironment by the kallikrein-related peptidases","volume":"22","author":"S Srinivasan","year":"2022","journal-title":"Nat Rev Cancer"},{"key":"pone.0305070.ref004","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.biochi.2015.09.002","article-title":"The kallikrein-related peptidase family: Dysregulation and functions during cancer progression","volume":"122","author":"T Kryza","year":"2016","journal-title":"Biochimie"},{"issue":"4","key":"pone.0305070.ref005","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3109\/10408363.2016.1154643","article-title":"Kallikrein-related peptidases (KLKs) and the hallmarks of cancer","volume":"53","author":"PS Filippou","year":"2016","journal-title":"Crit Rev Clin Lab Sci"},{"issue":"5","key":"pone.0305070.ref006","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/bju.15143","article-title":"Prostate-specific membrane antigen theranostics in advanced prostate cancer: an evolving option","volume":"126","author":"N Mayor","year":"2020","journal-title":"BJU Int"},{"issue":"4","key":"pone.0305070.ref007","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1515\/bc.2010.041","article-title":"Dysregulation of kallikrein-related peptidases in renal cell carcinoma: potential targets of miRNAs","volume":"391","author":"NM White","year":"2010","journal-title":"Biol Chem"},{"issue":"1","key":"pone.0305070.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000090150","article-title":"Prognostic implications of the immunohistochemical expression of human kallikreins 5, 6, 10 and 11 in renal cell carcinoma","volume":"27","author":"CD Petraki","year":"2006","journal-title":"Tumour Biol"},{"issue":"9","key":"pone.0305070.ref009","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.6004\/jnccn.2018.0072","article-title":"NCCN Guidelines Insights: Bladder Cancer, Version 5.2018","volume":"16","author":"TW Flaig","year":"2018","journal-title":"J Natl Compr Canc Netw"},{"issue":"25","key":"pone.0305070.ref010","doi-asserted-by":"crossref","first-page":"17876","DOI":"10.18632\/oncotarget.24947","article-title":"Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types","volume":"9","author":"PD Tailor","year":"2018","journal-title":"Oncotarget"},{"issue":"3","key":"pone.0305070.ref011","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1160\/TH13-03-0206","article-title":"Clinical utility of kallikrein-related peptidases (KLK) in urogenital malignancies","volume":"110","author":"J Dorn","year":"2013","journal-title":"Thromb Haemost"},{"issue":"6","key":"pone.0305070.ref012","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","volume":"38","author":"MJ Goldman","year":"2020","journal-title":"Nat Biotechnol"},{"issue":"6235","key":"pone.0305070.ref013","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans","volume":"348","author":"GTEx Consortium","year":"2015","journal-title":"Science"},{"issue":"1","key":"pone.0305070.ref014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1476-5586(04)80047-2","article-title":"ONCOMINE: a cancer microarray database and integrated data-mining platform","volume":"6","author":"DR Rhodes","year":"2004","journal-title":"Neoplasia"},{"issue":"W1","key":"pone.0305070.ref015","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Z Tang","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0305070.ref016","doi-asserted-by":"crossref","first-page":"9227","DOI":"10.1038\/s41598-018-27521-y","article-title":"Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets","volume":"8","author":"\u00c1 Nagy","year":"2018","journal-title":"Sci Rep"},{"issue":"269","key":"pone.0305070.ref017","first-page":"pl1","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"J Gao","year":"2013","journal-title":"Sci Signal"},{"issue":"Web Server issue","key":"pone.0305070.ref018","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"D Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pone.0305070.ref019","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"D Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"20","key":"pone.0305070.ref020","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1093\/bioinformatics\/btz210","article-title":"TISIDB: an integrated repository portal for tumor-immune system interactions","volume":"35","author":"B Ru","year":"2019","journal-title":"Bioinformatics"},{"key":"pone.0305070.ref021","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"S H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"issue":"4","key":"pone.0305070.ref022","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"G Bindea","year":"2013","journal-title":"Immunity"},{"issue":"1","key":"pone.0305070.ref023","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive analyses of tumor immunity: implications for cancer immunotherapy","volume":"17","author":"B Li","year":"2016","journal-title":"Genome Biol"},{"issue":"4","key":"pone.0305070.ref024","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nbt.3772","article-title":"Toil enables reproducible, open source, big biomedical data analyses","volume":"35","author":"J Vivian","year":"2017","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pone.0305070.ref025","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics","volume":"173","author":"J Liu","year":"2018","journal-title":"Cell"},{"issue":"16","key":"pone.0305070.ref026","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1158\/1078-0432.CCR-07-0143","article-title":"Secreted frizzled-related protein 1 loss contributes to tumor phenotype of clear cell renal cell carcinoma","volume":"13","author":"ML Gumz","year":"2007","journal-title":"Clin Cancer Res"},{"key":"pone.0305070.ref027","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1471-2407-3-31","article-title":"Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data","volume":"3","author":"ME Lenburg","year":"2003","journal-title":"BMC Cancer"},{"issue":"16","key":"pone.0305070.ref028","doi-asserted-by":"crossref","first-page":"5730","DOI":"10.1158\/1078-0432.CCR-04-2225","article-title":"Gene signatures of progression and metastasis in renal cell cancer","volume":"11","author":"J Jones","year":"2005","journal-title":"Clin Cancer Res"},{"issue":"6","key":"pone.0305070.ref029","doi-asserted-by":"crossref","first-page":"517","DOI":"10.7150\/ijbs.5.517","article-title":"Gene expression profiling of chromophobe renal cell carcinomas and renal oncocytomas by Affymetrix GeneChip using pooled and individual tumours","volume":"5","author":"MV Yusenko","year":"2009","journal-title":"Int J Biol Sci"},{"issue":"22","key":"pone.0305070.ref030","doi-asserted-by":"crossref","first-page":"7986","DOI":"10.1158\/1078-0432.CCR-05-1354","article-title":"Clear cell sarcoma of the kidney: up-regulation of neural markers with activation of the sonic hedgehog and Akt pathways","volume":"11","author":"C Cutcliffe","year":"2005","journal-title":"Clin Cancer Res"},{"issue":"11","key":"pone.0305070.ref031","doi-asserted-by":"crossref","first-page":"4674","DOI":"10.1158\/0008-5472.CAN-09-0146","article-title":"Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney","volume":"69","author":"R Beroukhim","year":"2009","journal-title":"Cancer Res"},{"key":"pone.0305070.ref032","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.semcancer.2018.03.005","article-title":"Ras and Rap1: A tale of two GTPases","volume":"54","author":"S Shah","year":"2019","journal-title":"Semin Cancer Biol"},{"issue":"6","key":"pone.0305070.ref033","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3390\/cancers10060154","article-title":"Treating p53 Mutant Aggregation-Associated Cancer","volume":"10","author":"M. Kanapathipillai","year":"2018","journal-title":"Cancers (Basel)"},{"issue":"5","key":"pone.0305070.ref034","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges","volume":"15","author":"D Fukumura","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"issue":"4","key":"pone.0305070.ref035","doi-asserted-by":"crossref","first-page":"357","DOI":"10.23736\/S0026-4806.17.05058-3","article-title":"The current management of renal cell carcinoma","volume":"108","author":"T Kuusk","year":"2017","journal-title":"Minerva Med"},{"issue":"4","key":"pone.0305070.ref036","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1056\/NEJMra1601333","article-title":"Systemic Therapy for Metastatic Renal-Cell Carcinoma","volume":"376","author":"TK Choueiri","year":"2017","journal-title":"N Engl J Med"},{"key":"pone.0305070.ref037","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.ejmech.2017.08.007","article-title":"Recent developments in small molecule therapies for renal cell carcinoma","volume":"142","author":"M. Song","year":"2017","journal-title":"Eur J Med Chem"},{"issue":"3","key":"pone.0305070.ref038","first-page":"1177","article-title":"Genetically\u2011modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)\u2011based targeted therapy (Review)","volume":"41","author":"M Devetzi","year":"2018","journal-title":"Int J Mol Med"},{"issue":"3","key":"pone.0305070.ref039","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nrd4534","article-title":"Unleashing the therapeutic potential of human kallikrein-related serine proteases","volume":"14","author":"I Prassas","year":"2015","journal-title":"Nat Rev Drug Discov"},{"issue":"3","key":"pone.0305070.ref040","first-page":"244","article-title":"Dysregulated KDR and FLT1 Gene Expression in Colorectal Cancer Patients","volume":"8","author":"F Mohammad Rezaei","year":"2019","journal-title":"Rep Biochem Mol Biol"},{"issue":"1","key":"pone.0305070.ref041","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3233\/TUB-211510","article-title":"Angiogenesis\u2019 related genetic variants alter clinical features and prognosis of diffuse large B-cell lymphoma patients","volume":"43","author":"ABC Brito","year":"2021","journal-title":"Tumour Biol"},{"issue":"2","key":"pone.0305070.ref042","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1158\/2326-6066.CIR-18-0442","article-title":"PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function","volume":"7","author":"S Whelan","year":"2019","journal-title":"Cancer Immunol Res"},{"issue":"1","key":"pone.0305070.ref043","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/imr.12530","article-title":"Potential targeting of B7-H4 for the treatment of cancer","volume":"276","author":"JR Podojil","year":"2017","journal-title":"Immunol Rev"},{"issue":"1","key":"pone.0305070.ref044","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s40001-024-01678-x","article-title":"DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications","volume":"29","author":"X Jing","year":"2024","journal-title":"Eur J Med Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305070","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T17:38:01Z","timestamp":1723138681000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0305070"}},"subtitle":[],"editor":[{"given":"Gurudeeban","family":"Selvaraj","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,8,8]]},"references-count":44,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0305070","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2024,8,8]]}}}