{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:13:10Z","timestamp":1789413190503,"version":"build-2803163510"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"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. Med."],"abstract":"<jats:p>With a worldwide prevalence of ~12%, pterygium is a common degenerative and environmentally triggered ocular surface disorder characterized by wing-shaped growth of conjunctival tissue onto the cornea that can lead to blindness if left untreated. This study characterizes the transcriptional profile and the cellular microenvironment of conjunctival pterygia and identifies novel pterygia-specific biomarkers. Formalin-fixed and paraffin-embedded pterygia as well as healthy conjunctival specimens were analyzed using MACE RNA sequencing (<jats:italic>n<\/jats:italic> = 8 each) and immunohistochemistry (pterygia <jats:italic>n<\/jats:italic> = 7, control <jats:italic>n<\/jats:italic> = 3). According to the bioinformatic cell type enrichment analysis using xCell, the cellular microenvironment of pterygia was characterized by an enrichment of myofibroblasts, T-lymphocytes and various antigen-presenting cells, including dendritic cells and macrophages. Differentially expressed genes that were increased in pterygia compared to control tissue were mainly involved in autophagy (including <jats:italic>DCN, TMBIM6<\/jats:italic>), cellular response to stress (including <jats:italic>TPT1, DDX5<\/jats:italic>) as well as fibroblast proliferation and epithelial to mesenchymal transition (including <jats:italic>CTNNB1, TGFBR1, and FN1<\/jats:italic>). Immunohistochemical analysis confirmed a significantly increased FN1 stromal immunoreactivity in pterygia when compared to control tissue. In addition, a variety of factors involved in apoptosis were significantly downregulated in pterygia, including <jats:italic>LCN2, CTSD<\/jats:italic>, and <jats:italic>NISCH<\/jats:italic>. Furthermore, 450 pterygia-specific biomarkers were identified by including transcriptional data of different ocular surface pathologies serving as controls (training group), which were then validated using transcriptional data of cultured human pterygium cells. Among the most pterygia-specific factors were transcripts such as <jats:italic>AHNAK, RTN4, TPT1, FSTL1<\/jats:italic>, and <jats:italic>SPARC<\/jats:italic>. Immunohistochemical validation of SPARC revealed a significantly increased stromal immunoreactivity in pterygia when compared to controls, most notably in vessels and intravascular vessel wall-adherent mononuclear cells. Taken together, the present study provides new insights into the cellular microenvironment and the transcriptional profile of pterygia, identifies new and specific biomarkers and in addition to fibrosis-related genes, uncovers autophagy, stress response and apoptosis modulation as pterygium-associated processes. These findings expand our understanding of the pathophysiology of pterygia, provide new diagnostic tools, and may enable new targeted therapeutic options for this common and sight-threatening ocular surface disease.<\/jats:p>","DOI":"10.3389\/fmed.2021.714458","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T04:56:48Z","timestamp":1643605008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Characterization of the Cellular Microenvironment and Novel Specific Biomarkers in Pterygia Using RNA Sequencing"],"prefix":"10.3389","volume":"8","author":[{"given":"Julian","family":"Wolf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rozina Ida","family":"Hajdu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefaniya","family":"Boneva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Schlecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thabo","family":"Lapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Wacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00fcrgen","family":"Agostini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Reinhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Auw-H\u00e4drich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnther","family":"Schlunck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.survophthal.2018.03.001","article-title":"Prevalence and risk factors of pterygium: a systematic review and meta-analysis","volume":"63","author":"Rezvan","year":"2018","journal-title":"Surv Ophthalmol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"567","DOI":"10.3109\/08820538.2014.971822","article-title":"Molecular basis of pterygium development","volume":"31","author":"Cardenas-Cantu","year":"2016","journal-title":"Semin Ophthalmol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"434","DOI":"10.2492\/inflammregen.28.434","article-title":"Epithelial-mesenchymal transition in the pathogenesis of pterygium","volume":"28","author":"Kato","year":"2008","journal-title":"Inflam Regene."},{"key":"B4","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1136\/bjophthalmol-2017-310288","article-title":"Comparison among adjuvant treatments for primary pterygium: a network meta-analysis","volume":"102","author":"Fonseca","year":"2017","journal-title":"Br J Ophthalmol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e097402","DOI":"10.1371\/journal.pone.0097402","article-title":"Evaluation of global differential gene and protein expression in primary pterygium: S100A8 and S100A9 as possible drivers of a signaling network","volume":"9","author":"Hou","year":"2014","journal-title":"PLoS ONE."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.1016\/j.yexcr.2013.08.022","article-title":"Comparison of gene expression profiles in primary and immortalized human pterygium fibroblast cells","volume":"319","author":"Hou","year":"2013","journal-title":"Exp Cell Res."},{"key":"B7","first-page":"2421","article-title":"Expression analysis of human pterygium shows a predominance of conjunctival and limbal markers and genes associated with cell migration","volume":"15","author":"Jaworski","year":"2009","journal-title":"Mol Vision."},{"key":"B8","first-page":"55","article-title":"Microarray and protein analysis of human pterygium","volume":"12","author":"John-Aryankalayil","year":"2006","journal-title":"Mol Vis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1002\/1873-3468.13027","article-title":"Linc-9432 is a novel pterygium lincRNA which regulates differentiation of fibroblasts","volume":"592","author":"Lan","year":"2018","journal-title":"Febs Lett."},{"key":"B10","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1755-8794-2-14","article-title":"Distinct gene subsets in pterygia formation and recurrence: dissecting complex biological phenomenon using genome wide expression data","volume":"2","author":"Tong","year":"2009","journal-title":"BMC Med Genomics."},{"key":"B11","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1186\/1471-2164-8-153","article-title":"Comparison of hybridization-based and sequencing-based gene expression technologies on biological replicates","volume":"8","author":"Liu","year":"2007","journal-title":"BMC Genomics."},{"key":"B12","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/nrg2934","article-title":"RNA sequencing: advances, challenges and opportunities","volume":"12","author":"Ozsolak","year":"2011","journal-title":"Nat Rev Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e39359","DOI":"10.1371\/journal.pone.0039359","article-title":"Molecular effects of doxycycline treatment on pterygium as revealed by massive transcriptome sequencing","volume":"7","author":"Larrayoz","year":"2012","journal-title":"PLoS ONE."},{"key":"B14","doi-asserted-by":"publisher","first-page":"7553","DOI":"10.1167\/iovs.14-14951","article-title":"Transcriptomic profiling explains racial disparities in pterygium patients treated with doxycycline","volume":"55","author":"Larrayoz","year":"2014","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"646550","DOI":"10.3389\/fgene.2021.646550","article-title":"Comparative transcriptomic analysis to identify the important coding and non-coding RNAs involved in the pathogenesis of pterygium","volume":"12","author":"Liu","year":"2021","journal-title":"Front Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e9056","DOI":"10.7717\/peerj.9056","article-title":"Transcriptional profiling to identify the key genes and pathways of pterygium","volume":"8","author":"Chen","year":"2020","journal-title":"PeerJ."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1038\/s41374-020-0446-z","article-title":"3' MACE RNA-sequencing allows for transcriptome profiling in human tissue samples after long-term storage","volume":"100","author":"Boneva","year":"2020","journal-title":"Lab Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"17022","DOI":"10.1038\/s41598-020-72864-0","article-title":"Transcriptional characterization of conjunctival melanoma identifies the cellular tumor microenvironment and prognostic gene signatures","volume":"10","author":"Wolf","year":"2020","journal-title":"Sci Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"21292","DOI":"10.1038\/s41598-020-78339-6","article-title":"MACE RNA sequencing analysis of conjunctival squamous cell carcinoma and papilloma using formalin-fixed paraffin-embedded tumor tissue","volume":"10","author":"Boneva","year":"2020","journal-title":"Sci Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1016\/j.ophtha.2012.03.037","article-title":"Enhanced TKTL1 expression in malignant tumors of the ocular adnexa predicts clinical outcome","volume":"119","author":"Lange","year":"2012","journal-title":"Ophthalmology."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1016\/j.ajpath.2020.04.004","article-title":"Transcriptomic characterization of human choroidal neovascular membranes identifies calprotectin as a novel biomarker for patients with age-related macular degeneration","volume":"190","author":"Schlecht","year":"2020","journal-title":"Am J Pathol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1038\/s41433-018-0172-6","article-title":"Increased expression of hypoxia-inducible factor-1 alpha and its impact on transcriptional changes and prognosis in malignant tumours of the ocular adnexa","volume":"32","author":"Lange","year":"2018","journal-title":"Eye (Lond)."},{"key":"B23","doi-asserted-by":"publisher","first-page":"W537","DOI":"10.1093\/nar\/gky379","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update","volume":"46","author":"Afgan","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/glia.23810","article-title":"Temporospatial distribution and transcriptional profile of retinal microglia in the oxygen-induced retinopathy mouse model","volume":"68","author":"Boeck","year":"2020","journal-title":"Glia."},{"key":"B25","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics."},{"key":"B26","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics."},{"key":"B27","doi-asserted-by":"publisher","first-page":"D682","DOI":"10.1093\/nar\/gkz966","article-title":"Ensembl 2020","volume":"48","author":"Yates","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics."},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"},{"key":"B31","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS."},{"key":"B32","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s12064-012-0162-3","article-title":"Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples","volume":"131","author":"Wagner","year":"2012","journal-title":"Theory Biosci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.exer.2015.07.009","article-title":"Myofibroblasts","volume":"142","author":"Hinz","year":"2016","journal-title":"Exp Eye Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.preteyeres.2017.08.001","article-title":"Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis","volume":"60","author":"Shu","year":"2017","journal-title":"Prog Retin Eye Res."},{"key":"B36","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":"B37","doi-asserted-by":"publisher","first-page":"e0151615","DOI":"10.1371\/journal.pone.0151615","article-title":"Individual case analysis of postmortem interval time on brain tissue preservation","volume":"11","author":"Blair","year":"2016","journal-title":"PLoS ONE."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2723","DOI":"10.3390\/ijms18122723","article-title":"Impact of methods on the measurement of mRNA turnover","volume":"18","author":"Wada","year":"2017","journal-title":"Int J Mol Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"409","DOI":"10.2353\/jmoldx.2010.090155","article-title":"Quantitative expression profiling in formalin-fixed paraffin-embedded samples by affymetrix microarrays","volume":"12","author":"Abdueva","year":"2010","journal-title":"J Mol Diagn."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1167\/iovs.06-1060","article-title":"Beta-catenin activation and epithelial-mesenchymal transition in the pathogenesis of pterygium","volume":"48","author":"Kato","year":"2007","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.3109\/02713683.2014.900806","article-title":"Inhibition of alpha-smooth muscle actin expression and migration of pterygium fibroblasts by coculture with amniotic mesenchymal stem cells","volume":"39","author":"Sha","year":"2014","journal-title":"Curr Eye Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1136\/bjo.2004.050633","article-title":"Characterisation of myofibroblasts in fibrovascular tissues of primary and recurrent pterygia","volume":"89","author":"Touhami","year":"2005","journal-title":"Br J Ophthalmol."},{"key":"B43","first-page":"153","article-title":"Pterygium: histological and immunohistochemical aspects","volume":"52","author":"Golu","year":"2011","journal-title":"Rom J Morphol Embryol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1076\/ocii.11.2.115.15913","article-title":"The roles of T-lymphocyte subpopulations (CD4 and CD8), intercellular adhesion molecule-1 (ICAM-1), HLA-DR receptor, and mast cells in etiopathogenesis of pterygium","volume":"11","author":"Beden","year":"2003","journal-title":"Ocul Immunol Inflamm."},{"key":"B45","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1159\/000095863","article-title":"Flow cytometrical analysis of adhesion molecules, T-lymphocyte subpopulations and inflammatory markers in pterygium","volume":"220","author":"Tekelioglu","year":"2006","journal-title":"Ophthalmologica."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1007\/s10792-020-01329-0","article-title":"Antigen-presenting cells in ocular surface diseases","volume":"40","author":"Kalogeropoulos","year":"2020","journal-title":"Int Ophthalmol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"L27","DOI":"10.1152\/ajplung.00510.2016","article-title":"Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma","volume":"313","author":"Liu","year":"2017","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"3885","DOI":"10.3892\/etm.2016.3908","article-title":"Expression of decorin in intestinal tissues of mice with inflammatory bowel disease and its correlation with autophagy","volume":"12","author":"Zhao","year":"2016","journal-title":"Exp Ther Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"6014","DOI":"10.1167\/iovs.18-25213","article-title":"Light-induced lipocalin 2 facilitates cellular apoptosis by positively regulating reactive oxygen species\/Bim signaling in retinal degeneration","volume":"59","author":"Tang","year":"2018","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2020.1752497","article-title":"Autophagy triggers CTSD (cathepsin D) maturation and localization inside cells to promote apoptosis","volume":"2020","author":"Di","year":"2020","journal-title":"Autophagy."},{"key":"B51","doi-asserted-by":"publisher","first-page":"663","DOI":"10.3892\/etm.2018.7017","article-title":"Nischarin attenuates apoptosis induced by oxidative stress in PC12 cells","volume":"17","author":"Guo","year":"2019","journal-title":"Exp Ther Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/1471-2407-13-65","article-title":"MYBBP1A suppresses breast cancer tumorigenesis by enhancing the p53 dependent anoikis","volume":"13","author":"Akaogi","year":"2013","journal-title":"BMC Cancer."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2767512","DOI":"10.1155\/2019\/2767512","article-title":"Identification and interaction analysis of significant genes and MicroRNAs in pterygium","volume":"2019","author":"He","year":"2019","journal-title":"Biomed Res Int."},{"key":"B54","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/cdd.2017.169","article-title":"How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?","volume":"2","author":"Aubrey","year":"2018","journal-title":"Cell Death Differ."},{"key":"B55","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1177\/1535370215579167","article-title":"Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy","volume":"240","author":"Dai","year":"2015","journal-title":"Experi Biol Med."},{"key":"B56","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1136\/bjo.84.2.212","article-title":"Apoptosis and apoptosis related gene expression in normal conjunctiva and pterygium","volume":"84","author":"Tan","year":"2000","journal-title":"Br J Ophthalmol."},{"key":"B57","first-page":"2522","article-title":"miR-455-3p functions as a tumor suppressor in colorectal cancer and inhibits cell proliferation by targeting TPT1","volume":"11","author":"Sun","year":"2018","journal-title":"Int J Clin Experi Pathol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2885","DOI":"10.1016\/j.bbrc.2018.08.063","article-title":"DDX5 promotes hepatocellular carcinoma tumorigenesis via Akt signaling pathway","volume":"503","author":"Xue","year":"2018","journal-title":"Biochem Biophys Res Commun."},{"key":"B59","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13045-018-0656-7","article-title":"The lncRNA NEAT1 activates Wnt\/beta-catenin signaling and promotes colorectal cancer progression via interacting with DDX5","volume":"11","author":"Zhang","year":"2018","journal-title":"J Hematol Oncol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"5725","DOI":"10.1038\/s41388-019-0824-4","article-title":"Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1","volume":"38","author":"He","year":"2019","journal-title":"Oncogene."},{"key":"B61","doi-asserted-by":"publisher","first-page":"6336","DOI":"10.1158\/1078-0432.CCR-16-2813","article-title":"miRomics and proteomics reveal a miR-296-3p\/PRKCA\/FAK\/Ras\/c-Myc feedback loop modulated by HDGF\/DDX5\/beta-catenin complex in lung adenocarcinoma","volume":"23","author":"Fu","year":"2017","journal-title":"Clin Cancer Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"4717","DOI":"10.1002\/jcb.26651","article-title":"Down-regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion","volume":"119","author":"Cai","year":"2018","journal-title":"J Cell Biochem."},{"key":"B63","doi-asserted-by":"publisher","first-page":"70211","DOI":"10.18632\/oncotarget.12191","article-title":"SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget."},{"key":"B64","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bph.13653","article-title":"The SPARC protein: an overview of its role in lung cancer and pulmonary fibrosis and its potential role in chronic airways disease","volume":"174","author":"Wong","year":"2017","journal-title":"Br J Pharmacol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1167\/iovs.11-7941","article-title":"Involvement of SPARC and MMP-3 in the pathogenesis of human pterygium","volume":"53","author":"Seet","year":"2012","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B66","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s12974-016-0657-9","article-title":"SPARC expression by cerebral microvascular endothelial cells in vitro and its influence on blood-brain barrier properties","volume":"13","author":"Alkabie","year":"2016","journal-title":"J Neuroinflammation."},{"key":"B67","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1189\/jlb.1105664","article-title":"SPARC is a VCAM-1 counter-ligand that mediates leukocyte transmigration","volume":"81","author":"Kelly","year":"2007","journal-title":"J Leukoc Biol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"14379","DOI":"10.1038\/s41598-018-32796-2","article-title":"Ahnak promotes tumor metastasis through transforming growth factor-\u03b2-mediated epithelial-mesenchymal transition","volume":"8","author":"Sohn","year":"2018","journal-title":"Sci Rep."},{"key":"B69","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.3892\/mmr.2015.3569","article-title":"Knockdown of reticulon 4C by lentivirus inhibits human colorectal cancer cell growth","volume":"12","author":"Xue","year":"2015","journal-title":"Mol Med Rep."},{"key":"B70","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/s41419-018-0695-6","article-title":"FSTL1 interacts with VIM and promotes colorectal cancer metastasis via activating the focal adhesion signalling pathway","volume":"9","author":"Gu","year":"2018","journal-title":"Cell Death Dis."},{"key":"B71","doi-asserted-by":"publisher","first-page":"109049","DOI":"10.1016\/j.abb.2021.109049","article-title":"SPARC knockdown attenuated TGF-beta1-induced fibrotic effects through Smad2\/3 pathways in human pterygium fibroblasts","volume":"713","author":"Fan","year":"2021","journal-title":"Arch Biochem Biophys."},{"key":"B72","doi-asserted-by":"publisher","first-page":"i436","DOI":"10.1093\/bioinformatics\/btz363","article-title":"Comprehensive evaluation of transcriptome-based cell-type quantification methods for immuno-oncology","volume":"35","author":"Sturm","year":"2019","journal-title":"Bioinformatics."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.714458\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T04:56:53Z","timestamp":1643605013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.714458\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":72,"alternative-id":["10.3389\/fmed.2021.714458"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.714458","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]},"article-number":"714458"}}