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Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 29868Article in journal (Refereed) PublishedText
Abstract [en]

Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

Place, publisher, year, edition, pages
2016. Vol. 6, 29868
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-301020DOI: 10.1038/srep29868ISI: 000379878300001PubMedID: 27430378OAI: oai:DiVA.org:uu-301020DiVA: diva2:953347
Funder
Swedish Cancer Society, CAN 2006/1078, CAN 2009/900, CAN 2012/438Swedish Research Council, K2007-66X-14936-04-3, K2010-67X-14936-07-3, K2013-66X-14936-10-5EU, FP7, Seventh Framework Programme
Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2016-08-17Bibliographically approved

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Bellomo, ClaudiaVanlandewijck, MichaelMoren, AnitaHeldin, Carl-HenrikMoustakas, Aristidis
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Science for Life Laboratory, SciLifeLabLudwig Institute for Cancer ResearchDepartment of Medical Biochemistry and MicrobiologyVascular Biology
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