{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:45:52Z","timestamp":1762508752473,"version":"3.40.5"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["#4162"],"award-info":[{"award-number":["#4162"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ftirma Kurumu","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour\u2010derived parathyroid hormone\u2010related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by <jats:italic>Pthlh<\/jats:italic>) gene expression and the impact of this relationship on cancer cachexia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed. <jats:italic>Pthlh<\/jats:italic> mRNA levels were measured by qRT\u2010PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour\u2010bearing mice received EGFR TKI erlotinib for 7\u00a0days via intraperitoneal injection or oral gavage. Tumour <jats:italic>Pthlh<\/jats:italic> mRNA, weight of fat\/muscle tissue, and grip strength were assessed. RNA\u2010seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of <jats:italic>PTHLH<\/jats:italic> and <jats:italic>EGFR<\/jats:italic> along with correlation analysis of <jats:italic>PTHLH<\/jats:italic> with <jats:italic>EGFR<\/jats:italic> and transforming growth factor alpha (<jats:italic>TGFA<\/jats:italic>) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to <jats:italic>PTHLH<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Expression of EGFR ligands, EGFR itself, and PTHrP co\u2010clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0005) while EGFR TKIs significantly decrease (90%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0005) <jats:italic>Pthlh<\/jats:italic> mRNA levels in LLC cells. <jats:italic>Pthlh<\/jats:italic> mRNA drops 65\u201375% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0005) in tumours upon treatment of LLC tumour\u2010bearing mice with erlotinib while their muscle mass and grip strength increase (9.2% <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, 23% <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.005, respectively) compared with tumour\u2010bearing control mice. <jats:italic>PTHLH<\/jats:italic> is overexpressed in tumours of LUSC (45.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and HNSC (17.5\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) compared with normal tissue. <jats:italic>PTHLH<\/jats:italic> expression correlates with <jats:italic>EGFR<\/jats:italic> and its ligand <jats:italic>TGFA<\/jats:italic> in both cancers (LUSC: <jats:italic>n<\/jats:italic>\u00a0=\u00a0745, <jats:italic>R<\/jats:italic>\u00a0=\u00a00.32, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001 and <jats:italic>R<\/jats:italic>\u00a0=\u00a00.51, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001; HNSC: <jats:italic>n<\/jats:italic>\u00a0=\u00a0545, <jats:italic>R<\/jats:italic>\u00a0=\u00a00.34, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001 and <jats:italic>R<\/jats:italic>\u00a0=\u00a00.50, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001, respectively). High <jats:italic>PTHLH<\/jats:italic> mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations (<jats:italic>n<\/jats:italic>\u00a0=\u00a040, log\u2010rank test, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0451).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour\u2010bearing mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12985","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T07:54:02Z","timestamp":1649058842000},"page":"1582-1594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of epidermal growth factor receptor suppresses parathyroid hormone\u2010related protein expression in tumours and ameliorates cancer\u2010associated cachexia"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3719-4673","authenticated-orcid":false,"given":"Bahar Zehra Camurdanoglu","family":"Weber","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics Koc University  Istanbul 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