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Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. 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 Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, and Department of Physiological Sciences, School of Medicine, University of Barcelona, ES-08908, Barcelona, Spain.
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, A-1090, Vienna, Austria.
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2018 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 25, no 5, p. 885-903Article in journal (Refereed) Published
Abstract [en]

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

Place, publisher, year, edition, pages
2018. Vol. 25, no 5, p. 885-903
National Category
Medical and Health Sciences Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-339262DOI: 10.1038/s41418-017-0021-3ISI: 000431770600007PubMedID: 29230000OAI: oai:DiVA.org:uu-339262DiVA, id: diva2:1175288
Funder
Swedish Cancer Society, CAN 2012/438; CAN 2015/438; CAN 2016/445; CAN 2012/1186Swedish Research Council, K2013-66X-14936-10-5; 2015-02757Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-06-29Bibliographically approved

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Bellomo, ClaudiaCaja, LaiaHeldin, Carl-HenrikMoustakas, Aristidis

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