Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition

The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe ho...

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Autores: López Luque, Judit, Bertran Rodríguez, Esther, Crosas Molist, Eva, Maiques, Oscar, Malfettone, Andrea, Caja Puigsubirà, Laia, Serrano Piñol, M. Teresa, Ramos Rubio, Emilio, Sanz Moreno, Victoria, Fabregat Romero, Isabel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/171982
Acceso en línea:https://hdl.handle.net/2445/171982
Access Level:acceso abierto
Palabra clave:Càncer
Genètica
Càncer de fetge
Factors de creixement
Metabolisme
Cancer
Genetics
Liver cancer
Growth factors
Metabolism
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spelling Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transitionLópez Luque, JuditBertran Rodríguez, EstherCrosas Molist, EvaMaiques, OscarMalfettone, AndreaCaja Puigsubirà, LaiaSerrano Piñol, M. TeresaRamos Rubio, EmilioSanz Moreno, VictoriaFabregat Romero, IsabelCàncerGenèticaCàncer de fetgeFactors de creixementMetabolismeCancerGeneticsLiver cancerGrowth factorsMetabolismThe Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.Elsevier B.V.2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion10 p.application/pdfhttps://hdl.handle.net/2445/171982Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.canlet.2019.08.011Cancer Letters, 2019, vol. 1 , num. 464, p. 15-24https://doi.org/10.1016/j.canlet.2019.08.011info:eu-repo/grantAgreement/EC/FP7/316549CC BY (c) Elsevier B.V., 2019http://creativecommons.org/licenses/by-cc-by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1719822026-05-29T05:05:01Z
dc.title.none.fl_str_mv Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
title Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
spellingShingle Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
López Luque, Judit
Càncer
Genètica
Càncer de fetge
Factors de creixement
Metabolisme
Cancer
Genetics
Liver cancer
Growth factors
Metabolism
title_short Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
title_full Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
title_fullStr Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
title_full_unstemmed Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
title_sort Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
dc.creator.none.fl_str_mv López Luque, Judit
Bertran Rodríguez, Esther
Crosas Molist, Eva
Maiques, Oscar
Malfettone, Andrea
Caja Puigsubirà, Laia
Serrano Piñol, M. Teresa
Ramos Rubio, Emilio
Sanz Moreno, Victoria
Fabregat Romero, Isabel
author López Luque, Judit
author_facet López Luque, Judit
Bertran Rodríguez, Esther
Crosas Molist, Eva
Maiques, Oscar
Malfettone, Andrea
Caja Puigsubirà, Laia
Serrano Piñol, M. Teresa
Ramos Rubio, Emilio
Sanz Moreno, Victoria
Fabregat Romero, Isabel
author_role author
author2 Bertran Rodríguez, Esther
Crosas Molist, Eva
Maiques, Oscar
Malfettone, Andrea
Caja Puigsubirà, Laia
Serrano Piñol, M. Teresa
Ramos Rubio, Emilio
Sanz Moreno, Victoria
Fabregat Romero, Isabel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Genètica
Càncer de fetge
Factors de creixement
Metabolisme
Cancer
Genetics
Liver cancer
Growth factors
Metabolism
topic Càncer
Genètica
Càncer de fetge
Factors de creixement
Metabolisme
Cancer
Genetics
Liver cancer
Growth factors
Metabolism
description The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/171982
url https://hdl.handle.net/2445/171982
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.canlet.2019.08.011
Cancer Letters, 2019, vol. 1 , num. 464, p. 15-24
https://doi.org/10.1016/j.canlet.2019.08.011
info:eu-repo/grantAgreement/EC/FP7/316549
dc.rights.none.fl_str_mv CC BY (c) Elsevier B.V., 2019
http://creativecommons.org/licenses/by-cc-by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv CC BY (c) Elsevier B.V., 2019
http://creativecommons.org/licenses/by-cc-by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403180735922176
score 15.812455

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