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TGFβ and LXR signaling in hepatocellular carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the Western world and in the Asia-pacific regions, with its incidence expected to rise up to 22 million cases till 2020. Hepatocellular carcinoma etiology is mainly due to hepatitis B (HBV) and hepatitis C (HCV) infections, and to a lesser extent it is determined by the development of alcohol-driven cirrhosis and non-alcoholic steatohepatitis (NASH). Furthermore, HCC is characterized by a high mortality rate, with poor prognostic expectance and limited therapeutic options currently available in the clinics.

Transforming growth factor beta (TGFβ) is a pleiotropic cytokine with a janus-role in HCC and in other malignancies. TGFβ can in fact elicit either tumor-suppressive and tumor- promoting effects depending on tumor stage, microenvironmental and immunological cues. In HCC specifically, TGFβ determines cytostasis and cellular senescence during the first stages of tumor development, while it enhances HCC malignancy and progression in the later stages due to increased invasiveness, acquired resistance to cytostatic actions and tumor immunotolerance.

Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are transcription factors of the nuclear hormone receptor family, which play an important role in oxysterol metabolism and reverse- cholesterol transport to the liver. Their involvement in malignancies has been studied so far to a limited extend, with evidence of both tumor-suppressive -via cytostatic mechanisms- and tumor- immunotolerance activities. Moreover, the potential crosstalk of LXR and TGFβ pathways has not been yet unraveled in the context of hepatocellular carcinoma.

We have described (Paper I) a high-content imaging platform for the screening of small molecules able to revert the TGFβ-induced epithelial to mesenchymal transition (EMT) in human keratinocytes. This screening allowed us to identify LXR agonists as epithelial plasticity modulators in established terminally differentiated and mouse embryonic fibroblast, as well as in epithelial and mesenchymal HCC cell lines.

We have identified (Paper II) the transcription factor SNAI1 (Snail) as the mediator of the crosstalk between TGFβ and LXRα pathways in epithelial and mesenchymal HCC cell models. LXRα activation diminishes the transcriptional induction of SNAI1 by TGFβ, thus antagonizing the induction of mesenchymal features and the production of reactive oxygen species by TGFβ. However, we have unraveled that LXRα and TGFβ signaling still positively interact in increasing cytostasis in HCC, in order to preserve liver epithelial features.

We have described (Paper III) that LXRα activation counteracts the transcriptional induction of α smooth muscle actin (αSMA), a major hallmark of fibroblast activation, elicited by TGFβ in patient-derived primary liver fibroblasts.

In conclusion, we herein report that the signaling crosstalk between TGFβ and LXRα pathways results in antagonistic effects either on parenchymal and fibroblast cell lines representative of the HCC disease, suggesting the potential future application of LXR agonists as clinical therapeutic options.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1406
Keyword [en]
Hepatocellular Carcinoma, high-throughput imaging, small molecules, epithelial plasticity, LXR, Snail, TGFβ, tumor suppression, reactive oxygen species, cancer-associated fibroblast, myofibroblast, Smad3, αSMA
National Category
Medical and Health Sciences Biochemistry and Molecular Biology Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-334408ISBN: 978-91-513-0175-4 (print)OAI: oai:DiVA.org:uu-334408DiVA, id: diva2:1159588
Public defence
2018-02-16, Room B41, BMC Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-01-10 Created: 2017-11-23 Last updated: 2018-03-07
List of papers
1. Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
Open this publication in new window or tab >>Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-301020 (URN)10.1038/srep29868 (DOI)000379878300001 ()27430378 (PubMedID)
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: 2017-12-05Bibliographically approved
2. Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
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(English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Article in journal (Refereed) Accepted
National Category
Cell Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334443 (URN)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-05
3. LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
Open this publication in new window or tab >>LXRα limits the pro-fibrotic action of TGFβ in liver cancer-associated fibroblasts
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(English)Manuscript (preprint) (Other academic)
National Category
Cell Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334448 (URN)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-05

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