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dc.contributor.authorJudge, Sarah M.en_US
dc.contributor.authorWu, Chia-Lingen_US
dc.contributor.authorBeharry, Adam W.en_US
dc.contributor.authorRoberts, Brandon M.en_US
dc.contributor.authorFerreira, Leonardo F.en_US
dc.contributor.authorKandarian, Susan C.en_US
dc.contributor.authorJudge, Andrew R.en_US
dc.coverage.spatialEnglanden_US
dc.date2014-12-11
dc.date.accessioned2018-02-27T17:41:22Z
dc.date.available2018-02-27T17:41:22Z
dc.date.issued2014-12-24
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/25539728
dc.identifier.citationSarah M Judge, Chia-Ling Wu, Adam W Beharry, Brandon M Roberts, Leonardo F Ferreira, Susan C Kandarian, Andrew R Judge. 2014. "Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia.." BMC Cancer, Volume 14, pp. 997 - ?.
dc.identifier.issn1471-2407
dc.identifier.urihttps://hdl.handle.net/2144/27317
dc.description.abstractBACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype. METHODS: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later. RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model. CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.en_US
dc.description.sponsorshipR01 AR060217 - NIAMS NIH HHS; R01 AR060209 - NIAMS NIH HHS; T32 HD043730 - NICHD NIH HHS; R00 HL098453 - NHLBI NIH HHS; R00HL098453 - NHLBI NIH HHS; R01AR060209 - NIAMS NIH HHS; R01AR060217 - NIAMS NIH HHSen_US
dc.format.extentp. 997en_US
dc.languageeng
dc.relation.ispartofBMC Cancer
dc.rights© Judge et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectScience & technologyen_US
dc.subjectLife sciences & biomedicineen_US
dc.subjectOncologyen_US
dc.subjectMuscle atrophyen_US
dc.subjectMicroarrayen_US
dc.subjectProteasomeen_US
dc.subjectCebpben_US
dc.subjectFosen_US
dc.subjectTranscription factorsen_US
dc.subjectZ-discen_US
dc.subjectExtracellular matrixen_US
dc.subjectProtein degradationen_US
dc.subjectMuscular dystrophyen_US
dc.subjectPancreatic canceren_US
dc.subjectAnimalsen_US
dc.subjectCachexiaen_US
dc.subjectColonic neoplasmsen_US
dc.subjectDependovirusen_US
dc.subjectDisease models, animalen_US
dc.subjectExtracellular matrixen_US
dc.subjectForkhead transcription factorsen_US
dc.subjectGene expression profilingen_US
dc.subjectGene expression regulationen_US
dc.subjectGene regulatory networksen_US
dc.subjectGenetic vectorsen_US
dc.subjectGenome-wide association studyen_US
dc.subjectHeterograftsen_US
dc.subjectHumansen_US
dc.subjectMaleen_US
dc.subjectMiceen_US
dc.subjectMolecular sequence dataen_US
dc.subjectMuscle, skeletalen_US
dc.subjectProteasome endopeptidase complexen_US
dc.subjectReproducibility of resultsen_US
dc.subjectSequence alignmenten_US
dc.subjectOncology and carcinogenesisen_US
dc.subjectOncology & carcinogenesisen_US
dc.titleGenome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexiaen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/1471-2407-14-997
pubs.elements-sourcepubmeden_US
pubs.notesEmbargo: No embargoen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Health & Rehabilitation Sciences: Sargent Collegeen_US
pubs.organisational-groupBoston University, College of Health & Rehabilitation Sciences: Sargent College, Health Sciencesen_US
pubs.organisational-groupBoston University, School of Medicineen_US
pubs.publication-statusPublished onlineen_US


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© Judge et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Except where otherwise noted, this item's license is described as © Judge et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.