The role of Caveolin-1 in the TGF-β-induced signalling in hepatocytes
[eng] The transforming growth factor-beta (TGF-β) is a cytokine involved in many physiological and pathological processes. Its dual role has been described in the liver, where it can either induce pro- or anti-apoptotic signals. The survival signals are in great extent mediated by the epidermal grow...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/102902 |
| Acceso en línea: | https://hdl.handle.net/2445/102902 http://hdl.handle.net/10803/396239 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer Càncer de fetge Cèl·lules hepàtiques Cancer Liver cancer Liver cells |
| Sumario: | [eng] The transforming growth factor-beta (TGF-β) is a cytokine involved in many physiological and pathological processes. Its dual role has been described in the liver, where it can either induce pro- or anti-apoptotic signals. The survival signals are in great extent mediated by the epidermal growth factor (EGFR). Caveolin-1 (CAV1) is a structural protein of the plasma membrane involved in the regulation of different signalling processes and receptor trafficking, as the TGF-β ones (TβRs). Traditionally, CAV1 has been associated with downregulation of the TGF-β signalling, given its presence in SMAD7 and SMURF2 positive vesicles. The great variety of functions associated with CAV1 has generated great controversy, as it acts differently depending on cell type. Regarding its role in the liver, CAV1 has been related to the SAMD-independent signals mediated by TGF-β and as an oncogene in hepatocellular carcinoma (HCC, its expression levels are increased in less differentiated tumours). Given the previously mentioned role of CAV1 in TβRs traffic and in the modulation of distinct signalling pathways, when we started this work, we hypothesized that the levels of CAV1 could be modulating the response to TGF-β in hepatocytes and in HCC cells, regulating the balance among pro- and anti-apoptotic signals induced by TGF-β in hepatocytes. Given this hypothesis, we proposed as an objective to study the role of CAV1 in the TGF-β-induced signalling in hepatocytes and in HCC cells. We decided to use an experimental cell model based on immortalized neonatal hepatocytes from CAV1-deficient mice (Cav1-/-) and we analyzed its response to TGF-β. We also used HCC cells in which CAV1 expression had been silenced or over-expressed, in regard to its basal expression levels. We observed that the lack of CAV1 both in foetal hepatocytes and in HCC cells impairs TGF-β-mediated EGFR transactivation, and in this way, cells are more sensitive to TGF-β pro-apoptotic effects. This is due to the fact that CAV1 is required for the proper activation of the metalloprotease TACE/ADAM17 by TGF-β, being responsible for the shedding of the EGFR ligands present in the plasma membrane as pro-ligands. Another important conclusion that we got was that the localization of TACE/ADAM17 in lipid raft domains is crucial for its activation, and this also requires CAV1. In HCC cells, CAV1 expression levels also determine the response to TGF-β in terms of death induction, but not in regard to cell cycle arrest. However, the final balance results in higher inhibition of the clonal growth by TGF-β when CAV1 expression is low. Another important result is that the induction of the death mediators NOX4, BMF and BIM by TGF-β is diminished when CAV1 expression levels in HCC cells are high. Finally, we have observed that CAV1 is required by the activation of Src and the NADPH oxidase-NOX1, both necessary for the activation of TACE/ADAM17 by TGF-β, being this the mechanism that explains the deficient EGFR transactivation observed both in hepatocytes and in HCC cells when CAV1 expression is low. To sum up this work, we can say that CAV1 levels condition the TGF-β-mediated anti-apoptotic response through the EGFR pathway. In HCC cells, this might be translated into a switch in the role of TGF-β: from anti- to pro-tumourigenic. |
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