{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:47:24Z","timestamp":1790178444972,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF) funded by the Korean government","award":["NRF 2020R1A2C1011455"],"award-info":[{"award-number":["NRF 2020R1A2C1011455"]}]},{"name":"National Research Foundation of Korea Grant funded by Korean Government","award":["2018R1D1A1B07051017"],"award-info":[{"award-number":["2018R1D1A1B07051017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>While a higher incidence of lung cancer in subjects with previous tuberculous infection has been reported in epidemiologic data, the mechanism by which previous tuberculosis affects lung cancer remains unclear. We investigated the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.Heat-killed Mycobacterium tuberculosis-stimulated mesothelial cells augmented the migrationand invasive potential of lung cancer cells in a NOX4-dependent manner. Mice with Mycobacterium bovis bacillus Calmette\u2013Gu\u00e9rin (BCG) pleural infection exhibited increased expression of NOX4 and enhanced malignant potential of lung cancer compared to mice with intrathoracic injection of phosphate-buffered saline. The BCG+ KLN205 (KLN205 cancer cell injection after BCG treatment) NOX4 KO mice group showed reduced tuberculous fibrosis-promoted metastatic potential of lung cancer, increased autophagy, and decreased expression of TGF-\u03b2, IL-6, and TNF-\u03b1 compared to the BCG+KLN205 WT mice group. Finally, NOX4 silencing mitigated the malignant potential of A549 cells that was enhanced by tuberculous pleural effusion and restored autophagy signaling. Our results suggest that the NOX4\u2013autophagy axis regulated by tuberculous fibrosis could result in enhanced tumorigenic potential and that NOX4-P62 might serve as a target for tuberculous fibrosis-induced lung cancer.<\/jats:p>","DOI":"10.3390\/cancers13040687","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T04:18:50Z","timestamp":1612844330000},"page":"687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Tuberculous Fibrosis Enhances Tumorigenic Potential via the NOX4\u2013Autophagy Axis"],"prefix":"10.3390","volume":"13","author":[{"given":"Seong Ji","family":"Woo","sequence":"first","affiliation":[{"name":"Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngmi","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-8403","authenticated-orcid":false,"given":"Harry","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-7706","authenticated-orcid":false,"given":"Ji Young","family":"Hong","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"},{"name":"Lung Research Institute, Hallym University College of Medicine, Chuncheon, Gangwon-do 24253, Korea"},{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon-si, Gangwon-do 24253, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2017). Global Tuberculosis Report 2017, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1038\/onc.2009.32","article-title":"Lung carcinogenesis induced by chronic tuberculosis infection: The experimental model and genetic control","volume":"28","author":"Nalbandian","year":"2009","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1183\/09031936.97.10040942","article-title":"Pleural tuberculosis","volume":"10","author":"Ferrer","year":"1997","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"L145","DOI":"10.1152\/ajplung.00348.2015","article-title":"Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis","volume":"311","author":"Yang","year":"2016","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kim, Y., Park, S.Y., Jung, H., Noh, Y.S., Lee, J.J., and Hong, J.Y. (2019). Inhibition of NADPH Oxidase 4 (NOX4) Signaling Attenuates Tuberculous Pleural Fibrosis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8010116"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4392","DOI":"10.18632\/oncotarget.2025","article-title":"NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K\/Akt signaling","volume":"5","author":"Zhang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.3892\/or.2016.4672","article-title":"MiR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4","volume":"35","author":"Sun","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"176","DOI":"10.4161\/gmic.20288","article-title":"Microbes-induced EMT at the crossroad of inflammation and cancer","volume":"3","author":"Hofman","year":"2012","journal-title":"Gut Microbes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1053\/j.gastro.2005.12.037","article-title":"Risk of intestinal cancer in inflammatory bowel disease: A population-based study from olmsted county, Minnesota","volume":"130","author":"Jess","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/ijc.28470","article-title":"Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer","volume":"134","author":"Yoshida","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_11","first-page":"185","article-title":"Association of lung carcinoma and tuberculosis","volume":"37","author":"Dacosta","year":"1991","journal-title":"J. Postgrad. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2169\/internalmedicine1962.28.471","article-title":"Prognosis of female patients with pulmonary tuberculosis","volume":"28","author":"Sakurai","year":"1989","journal-title":"Jpn. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1148\/119.2.307","article-title":"Lung carcinoma superimposed on pulmonary tuberculosis","volume":"119","author":"Ting","year":"1976","journal-title":"Radiology"},{"key":"ref_14","first-page":"405","article-title":"Pulmonary tuberculosis and coexisting carcinoma: A 10-year experience and review of the literature","volume":"41","author":"Gopalakrishnan","year":"1975","journal-title":"Am. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1177\/1534735403256332","article-title":"Inflammation as cause for scar cancers of the lung","volume":"2","author":"Ardies","year":"2003","journal-title":"Integr. Cancer Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1161\/CIRCRESAHA.109.193722","article-title":"Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells","volume":"105","author":"Lyle","year":"2009","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149185","DOI":"10.1155\/2014\/149185","article-title":"Chronic inflammation and cytokines in the tumor microenvironment","volume":"2014","author":"Landskron","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12943-019-1030-2","article-title":"Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy","volume":"18","author":"Chen","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, H., Wang, H., Wang, F., Gu, Q., and Xu, X. (2011). Snail involves in the transforming growth factor beta1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023322"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1038\/sj.onc.1210251","article-title":"Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells","volume":"26","author":"Kurashima","year":"2007","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1111\/j.1462-5822.2009.01422.x","article-title":"HIF-1alpha mediates the induction of IL-8 and VEGF expression on infection with Afa\/Dr diffusely adhering E. coli and promotes EMT-like behaviour","volume":"12","author":"Cane","year":"2010","journal-title":"Cell. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cellimm.2015.11.007","article-title":"Mycobacterium tuberculosis H37Rv infected THP-1 cells induce epithelial mesenchymal transition (EMT) in lung adenocarcinoma epithelial cell line (A549)","volume":"300","author":"Gupta","year":"2016","journal-title":"Cell. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/1476-4598-13-210","article-title":"Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-alpha-induced apoptosis","volume":"13","author":"Holla","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1089\/ars.2013.5608","article-title":"NADPH oxidases in lung health and disease","volume":"20","author":"Bernard","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1136\/thx.2009.113456","article-title":"NOX4\/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts","volume":"65","author":"Amara","year":"2010","journal-title":"Thorax"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1164\/rccm.201107-1281OC","article-title":"Increased nicotinamide adenine dinucleotide phosphate oxidase 4 expression mediates intrinsic airway smooth muscle hypercontractility in asthma","volume":"185","author":"Sutcliffe","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1165\/rcmb.2012-0242OC","article-title":"Role of nicotinamide adenine dinucleotide phosphate-reduced oxidase proteins in Pseudomonasaeruginosa-induced lung inflammation and permeability","volume":"48","author":"Fu","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"F159","DOI":"10.1152\/ajprenal.00546.2013","article-title":"RhoA\/Rho kinase mediates TGF-beta1-induced kidney myofibroblast activation through Poldip2\/Nox4-derived reactive oxygen species","volume":"307","author":"Manickam","year":"2014","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/ijc.25764","article-title":"Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells","volume":"129","author":"Gasche","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1084\/jem.182.1.243","article-title":"Interleukin 6 is essential for in vivo development of B lineage neoplasms","volume":"182","author":"Hilbert","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"964","DOI":"10.7150\/ijbs.4564","article-title":"Complexities of TGF-beta targeted cancer therapy","volume":"8","author":"Connolly","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1158\/0008-5472.CAN-11-3123","article-title":"Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1","volume":"72","author":"Li","year":"2012","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1158\/1541-7786.MCR-12-0160","article-title":"TNF-alpha induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3beta-dependent mechanism","volume":"10","author":"Ho","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/978-3-319-55330-6_16","article-title":"Functional Role of Nox4 in Autophagy","volume":"982","author":"Forte","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.taap.2013.07.013","article-title":"NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells","volume":"272","author":"Sobhakumari","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.phymed.2016.05.008","article-title":"Psoralidin induced reactive oxygen species (ROS)-dependent DNA damage and protective autophagy mediated by NOX4 in breast cancer cells","volume":"23","author":"Ren","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liu, X., Zhong, L., Li, P., and Zhao, P. (2020). MicroRNA-100 Enhances Autophagy and Suppresses Migration and Invasion of Renal Cell Carcinoma Cells via Disruption of NOX4-Dependent mTOR Pathway. Clin. Transl. Sci.","DOI":"10.1111\/cts.12798"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"507","DOI":"10.7326\/0003-4819-77-4-507","article-title":"Pleural effusions: The diagnostic separation of transudates and exudates","volume":"77","author":"Light","year":"1972","journal-title":"Ann. Intern. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3389\/fimmu.2018.00459","article-title":"Formation of Foamy Macrophages by Tuberculous Pleural Effusions Is Triggered by the Interleukin-10\/Signal Transducer and Activator of Transcription 3 Axis through ACAT Upregulation","volume":"9","author":"Genoula","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_40","first-page":"A1","article-title":"A Formaldehyde-Glutaraldehyde Fixative of High Osmolality for Use in Electron Microscopy","volume":"27","author":"Karnovsky","year":"1965","journal-title":"J. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1242\/jcs.094573","article-title":"Autophagy plays an essential role in the clearance of Pseudomonas aeruginosa by alveolar macrophages","volume":"125","author":"Yuan","year":"2012","journal-title":"J. Cell Sci."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/687\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:21:27Z","timestamp":1760160087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cancers13040687"],"URL":"https:\/\/doi.org\/10.3390\/cancers13040687","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]}}}