{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:01:26Z","timestamp":1789966886386,"version":"4.0.1"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oral Diseases"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Oral cancer, with a rising global incidence and poor prognosis, is associated with areca nut use in South and Southeast Asia. In this study, we addressed the effects of areca nut extract (ANE) on oral carcinogenesis by modulating fibroblast behavior in oral tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cell viability, migration, invasion, and flow cytometry assays were applied to study cell behaviors. Cytokine array, enzyme\u2010linked immunosorbent assay, phospho\u2010kinase array, Western blot analysis, and oxygen consumption and glycolysis assays were performed to evaluate cell functions. Immunohistochemical and immunofluorescent staining using human and hamster oral tissues was applied to validate in\u00a0vitro findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Increased alpha smooth muscle actin (\u03b1\u2010SMA) and fibroblast activation protein (FAP) were observed in fibroblasts from oral precancerous and cancer lesions. ANE increased mitochondrial metabolism in fibroblasts and induced myofibroblast transition. It enhanced epithelial\u2010to\u2010mesenchymal transition and granulocyte\u2010macrophage colony\u2010stimulating factor (GM\u2010CSF) secretion in fibroblasts. Conditioned medium from ANE\u2010treated fibroblasts and recombinant GM\u2010CSF increased epidermal growth factor receptor (EGFR) phosphorylation and malignant transformation in dysplastic oral keratinocytes. In hamsters, ANE treatment increased GM\u2010CSF expression in fibroblasts and EGFR phosphorylation in epithelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ANE promotes epithelial\u2010to\u2010mesenchymal transition and GM\u2010CSF secretion in fibroblasts, which activate EGFR signaling and malignant transformation of oral precancerous cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/odi.70236","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T09:34:03Z","timestamp":1771320843000},"page":"1889-1902","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic Reprogramming and\n                    <scp>GM<\/scp>\n                    \u2010\n                    <scp>CSF<\/scp>\n                    Secretion in Areca Nut\u2010Activated Fibroblasts Drive Oral Precancer Progression"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-4801","authenticated-orcid":false,"given":"Yen\u2010Yun","family":"Wang","sequence":"first","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Department of Medical Research Kaohsiung Medical University Hospital  Kaohsiung Taiwan"},{"name":"Drug Development and Value Creation Research Center Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang\u2010Wei","family":"Su","sequence":"additional","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Division of Oral and Maxillofacial Surgery Kaohsiung Medical University Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Huang","family":"Tseng","sequence":"additional","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Division of Oral Pathology &amp; Maxillofacial Radiology Kaohsiung Medical University Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pang\u2010Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine College of Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieu D. H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leong\u2010Perng","family":"Chan","sequence":"additional","affiliation":[{"name":"Cohort Research Center Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Faculty of Medicine College of Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Department of Otorhinolaryngology\u2010Head and Neck Surgery Kaohsiung Medical University Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuk\u2010Kwan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Division of Oral Pathology &amp; Maxillofacial Radiology Kaohsiung Medical University Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih Sheng","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research, National Health Research Institutes  Miaoli Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Lo","sequence":"additional","affiliation":[{"name":"Canniesburn Regional Plastic Surgery and Burns Unit  Glasgow UK"},{"name":"G4 0SF, College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4753-788X","authenticated-orcid":false,"given":"Shyng\u2010Shiou F.","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Dentistry College of Dental Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Department of Medical Research Kaohsiung Medical University Hospital  Kaohsiung Taiwan"},{"name":"Drug Development and Value Creation Research Center Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Graduate Institute of Medicine College of Medicine, Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Translational Research Center Kaohsiung Medical University Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016357.2013.871648"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/froh.2021.686337"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2021.105451"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins11040185"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1586\/era.10.108"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/15330338221146870"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2020.104972"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201018996\u20102"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2022.100557"},{"key":"e_1_2_12_11_1","first-page":"1","article-title":"Betel\u2010Quid and Areca\u2010Nut Chewing and Some Areca\u2010Nut Derived Nitrosamines","volume":"85","author":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, World Health Organization, and International Agency for Research on Cancer","year":"2004","journal-title":"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29636"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010020\u201000224\u20103"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u20100714.1995.tb01132.x"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkv077"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2006.10.003"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-015-1520-y"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.336"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349\u20107006.2009.01158.x"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033\u2010020\u201006054\u20106"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11188"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1148216"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12370"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12107"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oooo.2017.12.011"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.03.021"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910520225"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MR0521-763RR"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.13036"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010021\u201001698\u20105"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c00640"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2019.113713"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221092751"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12945"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201016080\u2010y"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910560327"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501293"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010024\u201003163\u2010z"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004343\u20109"}],"container-title":["Oral Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/odi.70236","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/odi.70236","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/odi.70236","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:13:15Z","timestamp":1789963995000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/odi.70236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":39,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/odi.70236"],"URL":"https:\/\/doi.org\/10.1111\/odi.70236","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/ODI.70236\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/ODI.70236\/v1\/review1","asserted-by":"object"}]},"ISSN":["1354-523X","1601-0825"],"issn-type":[{"value":"1354-523X","type":"print"},{"value":"1601-0825","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]},"assertion":[{"value":"2025-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}