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- Bellomo, Claudia, et al.
(författare)
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Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma
- 2018
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 25:5, s. 885-903
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Tidskriftsartikel (refereegranskat)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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- Giannelli, Gianluigi, et al.
(författare)
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The rationale for targeting TGF-beta in chronic liver diseases
- 2016
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 46:4, s. 349-361
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Forskningsöversikt (refereegranskat)abstract
- BackgroundTransforming growth factor (TGF)- is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF- is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF- is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear. DesignIn this review, we discuss the potential role of TGF- in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC. ResultsA considerable amount of experimental preclinical evidence suggests that TGF- is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF- pathway inhibitor, and results will soon be available. ConclusionsThe identification of new TGF- related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF- pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.
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- Morén, Anita, et al.
(författare)
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LXR alpha limits TGF beta-dependent hepatocellular carcinoma associated fibroblast differentiation
- 2019
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Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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