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Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2\u2010depleted metastatic OSCC mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2\u2010depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C\u2010reactive protein (CRP) levels, and survival were assessed. The activation of the IL6\/p38 pathway in atrophied muscle was measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IFIT2\u2010depleted metastatic tumours caused marked body weight loss (\u221218.2% vs. initial body weight, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and a poor survival rate (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Skeletal muscles were markedly smaller in IFIT2\u2010depleted metastatic tumour\u2010bearing mice (quadriceps: \u221228.7%, gastrocnemius: \u221229.4%, and tibialis: \u221224.3%, all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Tumour\u2010derived circulating granulocyte\u2010macrophage colony\u2010stimulating factor (+772.2\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), GRO\u03b1 (+1283.7\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), IL6 (+245.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), IL8 (+616.9\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), IL18 (+24\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), IP10 (+18.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), CCL2 (+439.2\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), CCL22 (+9.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and tumour necrosis factor \u03b1 (+196.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) were elevated in IFIT2\u2010depleted metastatic tumour\u2010bearing mice. Murine granulocyte colony\u2010stimulating factor (+61.4\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and IL6 (+110.9\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) levels were significantly increased in IFIT2\u2010depleted metastatic tumour\u2010bearing mice. Serum CRP level (+82.1%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (\u221226.7%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (\u221281%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and lean tissue (\u221221.7%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), which was consistent with the reduced food intake (\u221219.3%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Muscle loss was accompanied by a smaller muscle cross\u2010sectional area (\u221223.3%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Muscle atrophy of cachectic IFIT2\u2010depleted metastatic tumour\u2010bearing mice (i.v.\u2010shIFIT2 group) was associated with elevated IL6 (+2.7\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), phospho\u2010p38 (+2.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and atrogin\u20101 levels (+2.3\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium\u2010induced myotube atrophy (+24.6%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12943","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T03:14:14Z","timestamp":1644981254000},"page":"1314-1328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["IFIT2\u2010depleted metastatic oral squamous cell carcinoma cells induce muscle atrophy and cancer cachexia in mice"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1064-3216","authenticated-orcid":false,"given":"Kuo\u2010Chu","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, College of Medicine Chang Gung University  Taoyuan City Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine Chang Gung University  Taoyuan City Taiwan"},{"name":"Division of Hematology and Oncology, Department of Internal Medicine New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation)  New Taipei City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi\u2010Xuan","family":"Hong","sequence":"additional","affiliation":[{"name":"Masters Program in Pharmacology &amp; Toxicology, Department of Medicine, School of Medicine Tzu Chi University  Hualien Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyh\u2010Gang","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Family Medicine Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  Hualien Taiwan"},{"name":"Department of Medical Humanities, School of Medicine Tzu Chi University  Hualien Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui\u2010Ju","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Research and Development Immunwork, Inc.  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Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng\u2010Han","family":"Yang","sequence":"additional","affiliation":[{"name":"Deportment of Anatomic Pathology Chang Gung Memorial Hospital  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Masters Program in Pharmacology &amp; Toxicology, Department of Medicine, School of Medicine Tzu Chi University  Hualien 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