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LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation
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 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 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.
Univ Crete, Med Sch, Dept Biochem, Iraklion 71003, Crete, Greece.
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2019 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 8, article id 36Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGF beta and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGF beta signaling. We report that agonist-activated liver X receptors (LXR) limit the expression of key components of myofibroblast differentiation, including the a-smooth muscle actin (alpha SMA) gene in liver cancer cells. CAFs derived from hepatocellular carcinoma (HCC) express high aSMA and low LXR alpha levels, whereas hepatocarcinoma cells exhibit an inverse expression pattern. All hepatoma cells analyzed responded to the LXR alpha agonist T0901317 by inducing fatty acid synthase (FASN) expression. On the other hand, T0901317 antagonized TGF beta-induced fibroblastic marker responses, such as fibronectin and calponin, in a subset of hepatoma cells and all CAFs analyzed. Mechanistically, LXR alpha antagonized TGF beta signaling at the transcriptional level. Smad3 and LXR alpha were recruited to adjacent DNA motifs of the ACTA2 promoter. Upon cloning the human ACTA2 promoter, we confirmed its transcriptional induction by TGF beta stimulation, and LXR alpha overexpression repressed the promoter activity. Hepatosphere formation by HCC cells was enhanced upon co-culturing with CAFs. T0901317 suppressed the positive effects exerted on hepatosphere growth by CAFs. Taken together, the data suggest that LXR alpha agonists limit TGF beta-dependent CAF differentiation, potentially limiting primary HCC growth.

Place, publisher, year, edition, pages
2019. Vol. 8, article id 36
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-387277DOI: 10.1038/s41389-019-0140-4ISI: 000468075200001PubMedID: 31097694OAI: oai:DiVA.org:uu-387277DiVA, id: diva2:1329485
Funder
Swedish Research Council, K2013-66 x - 14936-10-5Swedish Research Council, 2017-01588Swedish Research Council, 2018-02757Swedish Research Council, 2015-02757EU, FP7, Seventh Framework ProgrammeEU, European Research Council, 787472Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved

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Morén, AnitaBellomo, ClaudiaTsubakihara, YutaroHeldin, Carl-HenrikMoustakas, Aristidis
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Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabLudwig Institute for Cancer Research
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