{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:14:57Z","timestamp":1792134897862,"version":"4.4.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"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. Genet."],"abstract":"<jats:p>Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis that affects female anogenital skin. Although VLS is considered a T cell-mediated autoimmune disease, the diagnosis criteria, molecular mechanism, and universally accepted therapies for this disease remain largely unresolved. To explore disease pathogenesis and potential biomarkers, we performed an RNA-Seq-based transcriptome analysis to profile the gene expression of VLS lesions. Differentially expressed gene (DEG) analysis revealed profound changes in expressions of coding genes, microRNAs, and long non-coding RNAs. Pathway and network analysis suggested that T cell activation-associated genes, including <jats:italic>CD3G<\/jats:italic>, <jats:italic>CD3D<\/jats:italic>, <jats:italic>CD8B<\/jats:italic>, <jats:italic>LAT<\/jats:italic>, <jats:italic>LCK<\/jats:italic>, <jats:italic>ZAP70<\/jats:italic>, <jats:italic>CCR5<\/jats:italic>, <jats:italic>CXCR3<\/jats:italic>, <jats:italic>CXCL9<\/jats:italic>, <jats:italic>CXCL10<\/jats:italic>, and <jats:italic>CXCL11<\/jats:italic>, were highly expressed in VLS, while <jats:italic>NR4A<\/jats:italic> family genes (<jats:italic>NR4A1<\/jats:italic>, <jats:italic>NR4A2<\/jats:italic>, <jats:italic>NR4A3<\/jats:italic>), whose coding products inhibit T cell activity, were significantly downregulated, suggesting heightened T cell response in VLS. Neutrophil chemoattractant genes <jats:italic>CXCL1<\/jats:italic>, <jats:italic>CXCL2<\/jats:italic>, <jats:italic>CXCL3<\/jats:italic>, <jats:italic>CXCL8<\/jats:italic>, and their cognate receptor <jats:italic>CXCR2<\/jats:italic> were downregulated, suggesting dampened neutrophil activity. We also found the downregulation of genes involved in cell cycle progression, including cyclins (<jats:italic>CCNB1<\/jats:italic>, <jats:italic>CCNB2<\/jats:italic>, <jats:italic>CCNL1<\/jats:italic>, <jats:italic>CCNE1<\/jats:italic>, and <jats:italic>CCNK<\/jats:italic>) and centrosome factors (<jats:italic>CENPA<\/jats:italic>, <jats:italic>CENPE<\/jats:italic>, <jats:italic>CENPF<\/jats:italic>, and <jats:italic>CENPN<\/jats:italic>), while microRNA-203a and let-7, microRNAs known to inhibit cell growth, were found to be upregulated. These data collectively indicate that cell proliferation in VLS is compromised. In sum, these findings comprehensively deciphered key regulatory genes and networks in VLS, which could further our understanding of disease mechanisms and point toward therapeutic strategies.<\/jats:p>","DOI":"10.3389\/fgene.2022.905450","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T04:29:01Z","timestamp":1655440141000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Transcriptome Profiling and Network Analysis Provide Insights Into the Pathogenesis of Vulvar Lichen Sclerosus"],"prefix":"10.3389","volume":"13","author":[{"given":"Lingyan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1533033819898729","DOI":"10.1177\/1533033819898729","article-title":"MiR-203a-3p Inhibits Pancreatic Cancer Cell Proliferation, EMT, and Apoptosis by Regulating SLUG","volume":"19","author":"An","year":"2020","journal-title":"Technol. Cancer Res. Treat."},{"key":"B2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.5114\/pdia.2016.56930","article-title":"Assessment of Systemic Inflammation with Neutrophil-Lymphocyte Ratio in Lichen Planus","volume":"33","author":"Atas","year":"2016","journal-title":"Postepy Dermatol Alergol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1046\/j.1365-2133.1999.02611.x","article-title":"Lichen Sclerosus in Adult Men: a Study of HLA Associations and Susceptibility to Autoimmune Disease","volume":"140","author":"Azurdia","year":"1999","journal-title":"Br. J. Dermatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/1471-2105-4-2","article-title":"An Automated Method for Finding Molecular Complexes in Large Protein Interaction Networks","volume":"4","author":"Bader","year":"2003","journal-title":"BMC Bioinforma."},{"key":"B5","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/s12016-018-8702-3","article-title":"The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis","volume":"55","author":"Blauvelt","year":"2018","journal-title":"Clin. Rev. Allerg. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/nrm1619","article-title":"The Cornified Envelope: a Model of Cell Death in the Skin","volume":"6","author":"Candi","year":"2005","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A Transcription Factors Limit CAR T Cell Function in Solid Tumours","volume":"567","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3892\/mmr.2013.1814","article-title":"MicroRNA-203 Inhibits the Proliferation and Invasion of U251 Glioblastoma Cells by Directly Targeting PLD2","volume":"9","author":"Chen","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"950","DOI":"10.3390\/biomedicines9080950","article-title":"Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects","volume":"9","author":"Corazza","year":"2021","journal-title":"Biomedicines"},{"key":"B10","doi-asserted-by":"publisher","first-page":"28301","DOI":"10.1038\/srep28301","article-title":"MiRNA-203 Suppresses Cell Proliferation, Migration and Invasion in Colorectal Cancer via Targeting of EIF5A2","volume":"6","author":"Deng","year":"2016","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s40257-012-0006-4","article-title":"Diagnosis and Treatment of Lichen Sclerosus","volume":"14","author":"Fistarol","year":"2013","journal-title":"Am. J. Clin. Dermatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.canlet.2004.12.028","article-title":"Centrosome Amplification, Chromosome Instability and Cancer Development","volume":"230","author":"Fukasawa","year":"2005","journal-title":"Cancer Lett."},{"key":"B13","first-page":"477","article-title":"Prevalence of Vulvar Lichen Sclerosus in a General Gynecology Practice","volume":"50","author":"Goldstein","year":"2005","journal-title":"J. Reprod. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"D380","DOI":"10.1093\/nar\/gkx1013","article-title":"TRRUST V2: an Expanded Reference Database of Human and Mouse Transcriptional Regulatory Interactions","volume":"46","author":"Han","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"7713","DOI":"10.1158\/0008-5472.can-07-1083","article-title":"The Let-7 microRNA Represses Cell Proliferation Pathways in Human Cells","volume":"67","author":"Johnson","year":"2007","journal-title":"Cancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil Recruitment and Function in Health and Inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1016\/j.bbamcr.2014.06.010","article-title":"NR4A Nuclear Receptors Are Orphans but Not Lonesome","volume":"1843","author":"Kurakula","year":"2014","journal-title":"Biochimica Biophysica Acta (BBA) - Mol. Cell. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/s41586-019-0979-8","article-title":"Genome-wide Analysis Identifies NR4A1 as a Key Mediator of T Cell Dysfunction","volume":"567","author":"Liu","year":"2019","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/1471-2164-11-224","article-title":"Intronic microRNAs Support Their Host Genes by Mediating Synergistic and Antagonistic Regulatory Effects","volume":"11","author":"Lutter","year":"2010","journal-title":"BMC Genomics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1365-2133.1995.tb05013.x","article-title":"The Association between Lichen Sclerosus and Antigens of the HLA System","volume":"132","author":"Marren","year":"1995","journal-title":"Br. J. Dermatol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"E577","DOI":"10.1073\/pnas.1102941108","article-title":"The D-Dopachrome Tautomerase (DDT) Gene Product Is a Cytokine and Functional Homolog of Macrophage Migration Inhibitory Factor (MIF)","volume":"108","author":"Merk","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B22","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1097\/cad.0000000000000874","article-title":"miR-203a Suppresses Cell Proliferation by Targeting RING-Finger Protein 6 in Colorectal Cancer","volume":"31","author":"Miao","year":"2020","journal-title":"Anticancer Drugs"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e30619","DOI":"10.1371\/journal.pone.0030619","article-title":"NGS QC Toolkit: a Toolkit for Quality Control of Next Generation Sequencing Data","volume":"7","author":"Patel","year":"2012","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1146\/annurev-biochem-060815-014528","article-title":"Mechanisms of Mitotic Spindle Assembly","volume":"85","author":"Petry","year":"2016","journal-title":"Annu. Rev. Biochem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.it.2019.05.001","article-title":"The Healing Power of Neutrophils","volume":"40","author":"Phillipson","year":"2019","journal-title":"Trends Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: a Comprehensive Platform Integrating Information on Human Disease-Associated Genes and Variants","volume":"45","author":"Pi\u00f1ero","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1016\/s0140-6736(98)08228-2","article-title":"Lichen Sclerosus","volume":"353","author":"Powell","year":"1999","journal-title":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2268","DOI":"10.1016\/j.juro.2007.08.024","article-title":"Lichen Sclerosus: Review of the Literature and Current Recommendations for Management","volume":"178","author":"Pugliese","year":"2007","journal-title":"J. Urology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.ejcb.2004.12.003","article-title":"Immune Dysregulation in Lichen Sclerosus","volume":"84","author":"Regauer","year":"2005","journal-title":"Eur. J. Cell. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma Powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706","article-title":"T Cell Activation","volume":"27","author":"Smith-Garvin","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"B32","doi-asserted-by":"publisher","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":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/jid.2011.369","article-title":"An Autoimmune Phenotype in Vulvar Lichen Sclerosus and Lichen Planus: a Th1 Response and High Levels of microRNA-155","volume":"132","author":"Terlou","year":"2012","journal-title":"J. Investigative Dermatology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.addr.2015.11.001","article-title":"Extracellular Matrix Structure","volume":"97","author":"Theocharis","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B35","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","article-title":"CXCL9, CXCL10, CXCL11\/CXCR3 axis for Immune Activation - A Target for Novel Cancer Therapy","volume":"63","author":"Tokunaga","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.7150\/ijbs.34613","article-title":"Lichen Sclerosus: An Autoimmunopathogenic and Genomic Enigma with Emerging Genetic and Immune Targets","volume":"15","author":"Tran","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/nprot.2012.016","article-title":"Differential Gene and Transcript Expression Analysis of RNA-Seq Experiments with TopHat and Cufflinks","volume":"7","author":"Trapnell","year":"2012","journal-title":"Nat. Protoc."},{"key":"B38","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1084\/jem.188.3.603","article-title":"Identification of C-C Chemokine Receptor 1 (CCR1) as the Monocyte Hemofiltrate C-C Chemokine (HCC)-1 Receptor","volume":"188","author":"Tsou","year":"1998","journal-title":"J. Exp. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.905450\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T04:29:07Z","timestamp":1655440147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.905450\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,17]]},"references-count":39,"alternative-id":["10.3389\/fgene.2022.905450"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.905450","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,17]]},"article-number":"905450"}}