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Cell Death Differ. 2018 May;25(5):885-903. doi: 10.1038/s41418-017-0021-3. Epub 2017 Dec 11.

Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma.

Author information

1
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123, Uppsala, Sweden.
2
Ludwig Institute for Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden.
3
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, and Department of Physiological Sciences, School of Medicine, University of Barcelona, ES-08908, Barcelona, Spain.
4
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, A-1090, Vienna, Austria.
5
Division of Basic Medical Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, GR-71003, Heraklion, Greece.
6
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123, Uppsala, Sweden. aris.moustakas@imbim.uu.se.
7
Ludwig Institute for Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden. aris.moustakas@imbim.uu.se.

Abstract

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.

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