New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Investigació Biomédica de Bellvitge (IDIBELL)

Detalles Bibliográficos
Autor: Caballero Díaz, Daniel
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/669195
Acceso en línea:http://hdl.handle.net/10803/669195
Access Level:acceso abierto
Palabra clave:Càncer de fetge
Cáncer de hígado
Liver cancer
Carcinogènesi
Carcinogénesis
Carcinogenesis
Proteïnes
Proteínas
Proteins
Factors de creixement
Factores de crecimiento
Growth factors
Ciències de la Salut
577
id ES_21efcdf6aaa3bb3ebb4f7fb4da5f0b5e
oai_identifier_str oai:www.tdx.cat:10803/669195
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
title New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
spellingShingle New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
Caballero Díaz, Daniel
Càncer de fetge
Cáncer de hígado
Liver cancer
Carcinogènesi
Carcinogénesis
Carcinogenesis
Proteïnes
Proteínas
Proteins
Factors de creixement
Factores de crecimiento
Growth factors
Ciències de la Salut
577
title_short New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
title_full New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
title_fullStr New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
title_full_unstemmed New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
title_sort New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesis
dc.creator.none.fl_str_mv Caballero Díaz, Daniel
author Caballero Díaz, Daniel
author_facet Caballero Díaz, Daniel
author_role author
dc.contributor.none.fl_str_mv Fabregat Romero, Isabel
Fabregat Romero, Isabel
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Càncer de fetge
Cáncer de hígado
Liver cancer
Carcinogènesi
Carcinogénesis
Carcinogenesis
Proteïnes
Proteínas
Proteins
Factors de creixement
Factores de crecimiento
Growth factors
Ciències de la Salut
577
topic Càncer de fetge
Cáncer de hígado
Liver cancer
Carcinogènesi
Carcinogénesis
Carcinogenesis
Proteïnes
Proteínas
Proteins
Factors de creixement
Factores de crecimiento
Growth factors
Ciències de la Salut
577
description Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Investigació Biomédica de Bellvitge (IDIBELL)
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/669195
url http://hdl.handle.net/10803/669195
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 240 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404547910205440
spelling New experimental approaches to study the relevance of the TGF-β and EGFR signalling during liver tumorigenesisCaballero Díaz, DanielCàncer de fetgeCáncer de hígadoLiver cancerCarcinogènesiCarcinogénesisCarcinogenesisProteïnesProteínasProteinsFactors de creixementFactores de crecimientoGrowth factorsCiències de la Salut577Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Investigació Biomédica de Bellvitge (IDIBELL)Hepatocellular Carcinoma (HCC) is one of the most common cancers. During hepatocarcinogenesis (a multistep process) there is a disruption of the balance between cell death and survival signalling pathways, where pro-apoptotic molecules are down-regulated/inactivated, and pro-survival pathways are over-activated. Some of these de-regulated signals are the Transforming Growth Factor beta (TGF-β) and the Epidermal Growth Factor Receptor (EGFR) pathway. The EGFR pathway is involved in the development and progression of hepatocarcinogenesis. EGF expression in the liver increases during cirrhosis and plays a role in both cirrhosis and HCC. In HCC cells, TGF-β can up-regulate the expression of different EGFR ligands and activate Src, Akt, and ERKs signalling pathways. The pro-tumorigenic cytokine TGF-β, is not the only pro-inflammatory molecule which EGFR interacts with. HCC is a clear example of inflammatory-related cancer and during the initial stages, exist chronic tissue damage and inflammation in the liver that result in overactivation of EGFR pathway. In addition, in HCC cells when EGFR pathway is down-regulated (by different mechanisms), the suppressor effects of TGF-β are coincident with increased up-regulation of NOX4 (NADPH-oxidases family member). In hepatocytes, NOX4 is required for the mitochondrial-mediated apoptosis induced by TGF-β and it acts as a negative regulator of cell growth in hepatocytes and liver tumour cells. Interestingly, EGF inhibits NOX4 expression acting at transcriptional level on NOX4 promoter. We have previously reported that EGFR pathway impairs the suppressor arm of TGF-β pathway in hepatocytes and liver tumour cells in vitro. Whether this effect may be relevant in vivo has not been explored yet. Furthermore, recent results have emphasized the essential role of intracellular trafficking proteins –caveolin-1 and clathrin– in the regulation of TGF-β and EGF receptors. However, less is known about how these proteins affects TGF-β and EGFR signalling pathways. Recently we reported that caveolin-1 is necessary for TGF-β induction of anti-apoptotic signalling in hepatocytes in a Src/NOX1-dependent manner. Furthermore, caveolin-1 has an essential role in switching the response to TGF-β from cytostatic to tumourigenic in liver tumour cells. Nevertheless, the role of clathrin in the crosstalk between these two signalling pathways and its relevance was barely known. To clear up the role of the EGFR in the process of hepatocarcinogenesis our group generated a novel transgenic mouse model expressing a hepatocyte-specific truncated form of the human EGFR, which acts as negative dominant mutant (∆EGFR) and allows defining its tyrosine kinase-dependent functions. These mice were treated with carbon tetrachloride (CCl4) to induce liver fibrosis or diethylnitrosamine (DEN) to induce liver tumorigenesis. Results presented here propose that EGFR is crucial in the first stages of liver fibrosis and hepatocarcinogenesis. Interestingly, the most relevant role of EGFR during both processes seems the regulation of the inflammatory liver environment. Hepatocytes and liver tumour cells have the ability to express pro- and/or anti-inflammatory signals whose balance would determinate the liver disease progression. In this process, the crosstalk with non-parenchymal cells, such as Kupffer cells or Hepatic Stellate cells, plays an essential role. Moreover, we show that trafficking proteins could have a significant role during the tumorigenic crosstalk between EGFR and TGF-β. In this context, clathrin may favour a switch of TGF-β to its anti-apoptotic role through EGFR, promoting survival and pro-tumorigenic advantages to liver cancer cells. Indeed, HCC patients present elevated levels of clathrin in tumoral tissue, highlighting its relevance for HCC progression. Chronic liver diseases are the consequence of deregulation in multifactor and multipath networks which articulate the molecular mechanisms that underlie liver tumorigenesis. This thesis proposes new insights about the role of inflammatory process and trafficking receptor proteins in the crosstalk between EGFR and TGF-β during liver chronic diseases.Universitat de BarcelonaFabregat Romero, IsabelFabregat Romero, IsabelUniversitat de Barcelona. Facultat de Medicina202020202018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion240 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/669195TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6691952026-06-14T12:46:07Z
score 15,300724

Similares en LA Referencia