{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T22:01:20Z","timestamp":1777500080371,"version":"3.51.4"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009326","name":"Cancer Research Society","doi-asserted-by":"publisher","award":["24328"],"award-info":[{"award-number":["24328"]}],"id":[{"id":"10.13039\/100009326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002383","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":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>CCAAT\/enhancer\u2010binding protein \u03b2 (C\/EBP\u03b2) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia\u2010inducing tumours, C\/EBP\u03b2 is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C\/EBP\u03b2 induces the expression of many secreted factors, including cytokines. Because tumour\u2010secreted factors drive cachexia and aggressive tumours have higher expression of C\/EBP\u03b2, we examined a potential role for C\/EBP\u03b2 in the expression of tumour\u2010derived cachexia\u2010inducing factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used gain\u2010of\u2010function and loss\u2010of\u2010function approaches <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> to evaluate the role of tumour C\/EBP\u03b2 expression on the secretion of cachexia\u2010inducing factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report that C\/EBP\u03b2 overexpression up\u2010regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (\u221231%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and myotube maturation [\u221238% (fusion index) and \u221225% (myotube diameter), <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05]. We find that knockdown of C\/EBP\u03b2 in cachexia\u2010inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and myotube diameter (+90%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) in conditioned medium experiments and, <jats:italic>in vivo<\/jats:italic>, prevents muscle wasting (\u221251% for small myofibres vs. controls, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; +140% for large myofibres, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Conversely, overexpression of C\/EBP\u03b2 in non\u2010cachectic tumours converts their secretome into a cachexia\u2010inducing one, resulting in reduced myotube diameter (\u221241%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001, EL4 model) and inhibition of differentiation in culture (\u221226%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01, EL4 model) and muscle wasting <jats:italic>in vivo<\/jats:italic> (+98% small fibres, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; \u221276% large fibres, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Comparison of the differently expressed transcripts coding for secreted proteins in C\/EBP\u03b2\u2010overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C\/EBP\u03b2\u2010regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up\u2010regulated by C\/EBP\u03b2. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (\u221233 to \u221236% for myotube diameter, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We find that C\/EBP\u03b2 is necessary and sufficient to induce the secretion of cachexia\u2010inducing factors by cancer cells and loss of C\/EBP\u03b2 in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C\/EBP\u03b2 as a central regulator of cancer cachexia and an important therapeutic target.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12909","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T05:27:35Z","timestamp":1641878855000},"page":"743-757","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["C\/EBP\u03b2 promotes the expression of atrophy\u2010inducing factors by tumours and is a central regulator of cancer cachexia"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-1392","authenticated-orcid":false,"given":"Hamood","family":"AlSudais","sequence":"first","affiliation":[{"name":"Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine University of Ottawa  Ottawa Ontario 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