{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:41:10Z","timestamp":1790188870832,"version":"4.1.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Discoidin, CUB, and LCCL domain-containing protein 2 (<jats:italic>DCBLD2<\/jats:italic>) is a two-domain transmembrane protein-coding gene located on chromosome 3, the protein expressed by which acts as the membrane receptor of semaphorin and vascular endothelial growth factor during the development of axons and blood vessels. Although several research evidences at the cellular and clinical levels have associated DCBLD2 with tumorigenesis, nothing is known regarding this gene from a pan-cancer standpoint. In this study, we systematically analyzed the influence of DCBLD2 on prognosis, cancer staging, immune characteristics, and drug sensitivity in a variety of cancers based on a unified and standardized pan-cancer dataset. In addition, we performed GO enrichment analyses and KEGG analyses of <jats:italic>DCBLD2<\/jats:italic>-related genes and DCBLD2-binding proteins. Our results showed that DCBLD2 is a potential oncogenic, immunological as well as a prognostic biomarker in terms of pan-cancer, and is expected to contribute to the improvement of tumor prognosis and the development of targeted therapy.<\/jats:p>","DOI":"10.3389\/fphar.2022.950831","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T09:50:34Z","timestamp":1660211434000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Pan-cancer analyses identify DCBLD2 as an oncogenic, immunological, and prognostic biomarker"],"prefix":"10.3389","volume":"13","author":[{"given":"Pan","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Long","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Qian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12861","DOI":"10.1038\/s41598-021-92026-0","article-title":"A homozygous nonsense mutation in DCBLD2 is a candidate cause of developmental delay, dysmorphic features and restrictive cardiomyopathy.","volume":"11","author":"Alhamoudi","year":"2021","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the\u00a0population abundance of tissue-infiltrating immune and stromal cell populations using gene expression.","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/j.cell.2018.03.059","article-title":"SnapShot: TCGA-analyzed tumors.","volume":"173","author":"Blum","year":"2018","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","article-title":"Pan-cancer analysis of whole genomes [J]","volume":"578","author":"Campbell","year":"2020","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"D1056","DOI":"10.1093\/nar\/gky1133","article-title":"Open targets platform: New developments and updates two years on.","volume":"47","author":"Carvalho-Silva","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.neo.2017.05.002","article-title":"Ualcan: A portal for facilitating tumor subgroup gene expression and survival analyses.","volume":"19","author":"Chandrashekar","year":"2017","journal-title":"Neoplasia (New York, NY)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade.","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.3390\/cancers13061403","article-title":"DCBLD2 mediates epithelial-mesenchymal transition-induced metastasis by cisplatin in lung adenocarcinoma","volume":"13","author":"Chen","year":"2021","journal-title":"Cancers"},{"key":"B9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.canlet.2021.04.005","article-title":"ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.","volume":"510","author":"Coppo","year":"2021","journal-title":"Cancer Lett."},{"key":"B10","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1186\/1471-2105-12-298","article-title":"GPS-prot: A web-based visualization platform for integrating host-pathogen interaction data.","volume":"12","author":"Fahey","year":"2011","journal-title":"BMC Bioinforma."},{"key":"B11","doi-asserted-by":"publisher","first-page":"7544","DOI":"10.26355\/eurrev_202007_22181","article-title":"MiR-150 alleviates EMT and cell invasion of colorectal cancer through targeting Gli1.","volume":"24","author":"Fan","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3140","DOI":"10.1002\/ijc.32369","article-title":"ROCplot.org: Validating predictive biomarkers of chemotherapy\/hormonal therapy\/anti-HER2 therapy using transcriptomic data of 3, 104 breast cancer patients.","volume":"145","author":"Fekete","year":"2019","journal-title":"Int. J. Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"3741","DOI":"10.1172\/JCI73093","article-title":"EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.","volume":"124","author":"Feng","year":"2014","journal-title":"J. Clin. Invest."},{"key":"B14","doi-asserted-by":"publisher","first-page":"659168","DOI":"10.3389\/fmolb.2021.659168","article-title":"Transcriptomic profiling identifies DCBLD2 as a diagnostic and prognostic biomarker in pancreatic ductal adenocarcinoma.","volume":"8","author":"Feng","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s12967-020-02527-1","article-title":"Development and validation of a cancer stem cell-related signature for prognostic prediction in pancreatic ductal adenocarcinoma.","volume":"18","author":"Feng","year":"2020","journal-title":"J. Transl. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s13073-020-0721-z","article-title":"Large-scale public data reuse to model immunotherapy response and resistance.","volume":"12","author":"Fu","year":"2020","journal-title":"Genome Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ni.2703","article-title":"Innate and adaptive immune cells in the tumor microenvironment.","volume":"14","author":"Gajewski","year":"2013","journal-title":"Nat. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"B19","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s13402-020-00495-8","article-title":"Association of DCBLD2 upregulation with tumor progression and poor survival in colorectal cancer.","volume":"43","author":"He","year":"2020","journal-title":"Cell. Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"B21","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1126\/science.aaa6204","article-title":"T cell exclusion, immune privilege, and the tumor microenvironment.","volume":"348","author":"Joyce","year":"2015","journal-title":"Sci. (New York, NY)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/j.bbapap.2017.06.023","article-title":"Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is a novel biomarker of myxofibrosarcoma invasion identified by global protein expression profiling.","volume":"1865","author":"Kikuta","year":"2017","journal-title":"Biochim. Biophys. Acta. Proteins Proteom."},{"key":"B23","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1158\/1541-7786.MCR-07-0142","article-title":"Epigenetic down-regulation and suppressive role of DCBLD2 in gastric cancer cell proliferation and invasion.","volume":"6","author":"Kim","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.addr.2015.11.009","article-title":"Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy.","volume":"99","author":"Komohara","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2822","DOI":"10.1038\/sj.onc.1205405","article-title":"Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as in lung cancers in vivo.","volume":"21","author":"Koshikawa","year":"2002","journal-title":"Oncogene"},{"key":"B26","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells.","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1093\/bioinformatics\/bty411","article-title":"GSCALite: A web server for gene set cancer analysis.","volume":"34","author":"Liu","year":"2018","journal-title":"Bioinforma. Oxf. Engl."},{"key":"B28","doi-asserted-by":"publisher","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":"Liu","year":"2018","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1007\/s00109-015-1376-x","article-title":"Immunosuppressive cells in tumor immune escape and metastasis.","volume":"94","author":"Liu","year":"2016","journal-title":"J. Mol. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2021\/6661406","article-title":"Current and future perspectives of PD-1\/PDL-1 blockade in cancer immunotherapy","author":"Makuku","year":"2021","journal-title":"J. Immunol. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"84","DOI":"10.7150\/jca.5482","article-title":"Tumor-infiltrating immune cells promoting tumor invasion and metastasis: Existing theories.","volume":"4","author":"Man","year":"2013","journal-title":"J. Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.3389\/fimmu.2019.01835","article-title":"The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4025","DOI":"10.1038\/sj.onc.1210183","article-title":"CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells.","volume":"26","author":"Nagai","year":"2007","journal-title":"Oncogene"},{"key":"B34","doi-asserted-by":"publisher","first-page":"5082","DOI":"10.1172\/JCI67752","article-title":"Transmembrane protein ESDN promotes endothelial VEGF signaling and regulates angiogenesis.","volume":"123","author":"Nie","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B35","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1093\/bioinformatics\/btt607","article-title":"Protter: Interactive protein feature visualization and integration with experimental proteomic data.","volume":"30","author":"Omasits","year":"2014","journal-title":"Bioinforma. Oxf. Engl."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0201751","DOI":"10.1371\/journal.pone.0201751","article-title":"Pancreatic cancer survival analysis defines a signature that predicts outcome.","volume":"13","author":"Raman","year":"2018","journal-title":"PloS one"},{"key":"B37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-981-16-5812-9_2","volume-title":"The GeneCards suite [M]\/\/ABUGESSAISA I, KASUKAWA T. Practical guide to Life science databases","author":"Safran","year":"2021"},{"key":"B38","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1042\/BCJ20190022","article-title":"The DCBLD receptor family: Emerging signaling roles in development, homeostasis and disease.","volume":"476","author":"Schmoker","year":"2019","journal-title":"Biochem. J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1074\/mcp.RA120.002163","article-title":"FYN and ABL regulate the interaction networks of the DCBLD receptor family.","volume":"19","author":"Schmoker","year":"2020","journal-title":"Mol. Cell. Proteomics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"E642","DOI":"10.3390\/jcm8050642","article-title":"Consequences of EMT-driven changes in the immune microenvironment of breast cancer and therapeutic response of cancer cells.","volume":"8","author":"Singh","year":"2019","journal-title":"J. Clin. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets.","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.canlet.2015.10.009","article-title":"Immunotherapy and tumor microenvironment.","volume":"370","author":"Tang","year":"2016","journal-title":"Cancer Lett."},{"key":"B43","doi-asserted-by":"publisher","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis.","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1002\/1878-0261.12093","article-title":"New insights into the role of EMT in tumor immune escape.","volume":"11","author":"Terry","year":"2017","journal-title":"Mol. Oncol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune checkpoint blockade: A common denominator approach to cancer therapy.","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome.","volume":"347","author":"Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The cancer Genome Atlas pan-cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."},{"key":"B48","doi-asserted-by":"publisher","first-page":"5904","DOI":"10.1038\/onc.2008.271","article-title":"The tumor microenvironment and its role in promoting tumor growth.","volume":"27","author":"Whiteside","year":"2008","journal-title":"Oncogene"},{"key":"B49","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.canlet.2016.01.043","article-title":"Tumor microenvironment and therapeutic response.","volume":"387","author":"Wu","year":"2017","journal-title":"Cancer Lett."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data.","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat. Commun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.clim.2008.12.006","article-title":"Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease.","volume":"131","author":"Yu","year":"2009","journal-title":"Clin. Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.3389\/fonc.2020.01066","article-title":"VCAM1 promotes tumor cell invasion and metastasis by inducing EMT and transendothelial migration in colorectal cancer.","volume":"10","author":"Zhang","year":"2020","journal-title":"Front. Oncol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.950831\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T09:50:37Z","timestamp":1660211437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.950831\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,11]]},"references-count":52,"alternative-id":["10.3389\/fphar.2022.950831"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.950831","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,11]]},"article-number":"950831"}}