{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T08:47:52Z","timestamp":1782982072124,"version":"3.54.5"},"reference-count":32,"publisher":"The Korean Academy of Tuberculosis and Respiratory Diseases","issue":"3","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Korean Academy of Tuberculosis and Respiratory Diseases"}],"content-domain":{"domain":["e-trd.org"],"crossmark-restriction":true},"short-container-title":["Tuberc Respir Dis"],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>Background: Lung cancer remains the leading cause of cancer-related mortality, with poor outcomes driven by late presentation and therapy resistance. While genes encoding secreted proteins may reflect tumor biology and have biomarker potential, systematic multi-cohort studies that identify and validate prognostically relevant secreted protein candidates in non-small cell lung cancer (NSCLC) are limited.Methods: We conducted a multi-cohort transcriptomic screen of 1,896 genes encoding secreted proteins to nominate prognostic candidates in NSCLC. Candidates were prioritized based on differential expression between tumor and normal tissues and survival associations across public NSCLC cohorts. Serpin family A member 3 (&lt;i&gt;SERPINA3&lt;\/i&gt;) was selected for further validation in The Cancer Genome Atlas (TCGA) NSCLC dataset. Tumors were stratified by &lt;i&gt;SERPINA3&lt;\/i&gt; expression for Kaplan\u2013Meier survival analysis and gene set enrichment analysis (GSEA) using the Hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) collections. Translational relevance was assessed in a retrospective bronchoalveolar lavage fluid (BALF) registry using multivariable Cox models.Results: In the TCGA NSCLC dataset, &lt;i&gt;SERPINA3&lt;\/i&gt;-high tumors had shorter overall survival (OS; log-rank p=0.016) and progression-free survival (PFS; log-rank p=0.018). GSEA showed enrichment in tumor necrosis factor-\u03b1\/nuclear factor-\u03baB, inflammatory response, interleukin 6 (IL-6)\u2013Janus kinase (JAK)\u2013signal transducer and activator of transcription 3 (STAT3), and IL-17 signaling pathways. The &lt;i&gt;SERPINA3&lt;\/i&gt;-high state exhibited a T-cell\u2013infiltrated, checkpoint-high phenotype consistent with T-cell dysfunction, characterized by increased levels of transforming growth factor-\u03b2, IL-10, and indoleamine 2,3-dioxygenase (IDO). In the BALF registry, higher BALF\u2014but not plasma\u2014&lt;i&gt;SERPINA3&lt;\/i&gt; independently predicted shorter PFS, with a nonsignificant trend toward OS after adjustment.Conclusion: Across datasets, &lt;i&gt;SERPINA3&lt;\/i&gt; indicates an immune-inflammatory tumor state associated with worse survival. BALF-based measurement captured tumor-proximal signals that may be less apparent in plasma, supporting its potential clinical utility for risk stratification and warranting prospective validation.<\/jats:p>","DOI":"10.4046\/trd.2026.0014","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:10:22Z","timestamp":1779091822000},"page":"403-415","update-policy":"https:\/\/doi.org\/10.4046\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SERPINA3 as a Secreted-Protein Biomarker Associated with Poor Prognosis and T-Cell Dysfunction in Non-small Cell Lung Cancer"],"prefix":"10.4046","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1757-4380","authenticated-orcid":true,"given":"Joon","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"},{"name":"Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geunin","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hyun","family":"Yong","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunju","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wooju","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongryeol","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6681-4478","authenticated-orcid":true,"given":"Chang-Myung","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-5318","authenticated-orcid":true,"given":"Sang Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2481","reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","type":"journal-article"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","type":"journal-article"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871","type":"journal-article"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2025.264","type":"journal-article"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-025-03519-z","type":"journal-article"},{"key":"ref6","first-page":"1379","type":"journal-article","volume-title":"Breast tumor microenvironment: proteomics highlights the treatments targeting secretome","author":"Chen","year":"2008"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2010.09.001","type":"journal-article"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-025-03302-0","type":"journal-article"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18794-x","type":"journal-article"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2019.00160","type":"journal-article"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11010156","type":"journal-article"},{"key":"ref12","first-page":"e12980","type":"journal-article","volume-title":"Regulation of CNS pathology by Serpina3n\/SERPINA3: the knowns and the puzzles","author":"Zhu","year":"2024"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2022.188760","type":"journal-article"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-019-0288-8","type":"journal-article"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9409","type":"journal-article"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-021-01221-4","type":"journal-article"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217217","type":"journal-article"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-023-01763-w","type":"journal-article"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1002\/iid3.515","type":"journal-article"},{"key":"ref20","first-page":"96","type":"journal-article","volume-title":"Overexpression of SERPINA3 suppresses tumor progression by modulating SPOP\/NF-kB in lung cancer","author":"Jin","year":"2023"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-024-00829-w","type":"journal-article"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1024508","type":"journal-article"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2016.10.016","type":"journal-article"},{"key":"ref24","first-page":"1260419","type":"journal-article","volume-title":"Proteomics: tissue-based map of the human proteome","author":"Uhlen","year":"2015"},{"key":"ref25","first-page":"807","type":"journal-article","volume-title":"Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer","author":"Ravi","year":"2023"},{"key":"ref26","first-page":"998","type":"journal-article","volume-title":"Defining T cell states associated with response to checkpoint immunotherapy in melanoma","author":"Sade-Feldman","year":"2018"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2025.102419","type":"journal-article"},{"key":"ref28","first-page":"1348","type":"journal-article","volume-title":"SERPINA3 promotes endometrial cancer cells growth by regulating G2\/M cell cycle checkpoint and apoptosis","author":"Yang","year":"2014"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.70078","type":"journal-article"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2023.0381","type":"journal-article"},{"key":"ref31","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-24-392","type":"journal-article"},{"key":"ref32","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2010.80","type":"journal-article"}],"container-title":["Tuberculosis and Respiratory Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/e-trd.org\/upload\/pdf\/trd-2026-0014.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/e-trd.org\/journal\/view.php?doi=10.4046\/trd.2026.0014","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/e-trd.org\/upload\/pdf\/trd-2026-0014.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T08:18:32Z","timestamp":1782980312000},"score":1,"resource":{"primary":{"URL":"http:\/\/e-trd.org\/journal\/view.php?doi=10.4046\/trd.2026.0014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":32,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,7]]}},"URL":"https:\/\/doi.org\/10.4046\/trd.2026.0014","relation":{},"ISSN":["1738-3536","2005-6184"],"issn-type":[{"value":"1738-3536","type":"print"},{"value":"2005-6184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"2026-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-18","order":2,"name":"published","label":"Published online","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-01","order":3,"name":"published","label":"Print publication","group":{"name":"publication_history","label":"Publication History"}}]}}