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Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer

Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain...

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Autores principales: Bárcena, Cristina, Stefanovic, Milica, Tutusaus, Anna, Martinez-Nieto, Guillermo A., Martinez, Laura, García-Ruiz, Carmen, de Mingo, Alvaro, Caballeria, Juan, Fernandez-Checa, José C., Marí, Montserrat, Morales, Albert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300499/
https://www.ncbi.nlm.nih.gov/pubmed/25604905
http://dx.doi.org/10.1038/srep07916
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author Bárcena, Cristina
Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Martinez, Laura
García-Ruiz, Carmen
de Mingo, Alvaro
Caballeria, Juan
Fernandez-Checa, José C.
Marí, Montserrat
Morales, Albert
author_facet Bárcena, Cristina
Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Martinez, Laura
García-Ruiz, Carmen
de Mingo, Alvaro
Caballeria, Juan
Fernandez-Checa, José C.
Marí, Montserrat
Morales, Albert
author_sort Bárcena, Cristina
collection PubMed
description Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management.
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spelling pubmed-43004992015-01-27 Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer Bárcena, Cristina Stefanovic, Milica Tutusaus, Anna Martinez-Nieto, Guillermo A. Martinez, Laura García-Ruiz, Carmen de Mingo, Alvaro Caballeria, Juan Fernandez-Checa, José C. Marí, Montserrat Morales, Albert Sci Rep Article Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management. Nature Publishing Group 2015-01-21 /pmc/articles/PMC4300499/ /pubmed/25604905 http://dx.doi.org/10.1038/srep07916 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Bárcena, Cristina
Stefanovic, Milica
Tutusaus, Anna
Martinez-Nieto, Guillermo A.
Martinez, Laura
García-Ruiz, Carmen
de Mingo, Alvaro
Caballeria, Juan
Fernandez-Checa, José C.
Marí, Montserrat
Morales, Albert
Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title_full Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title_fullStr Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title_full_unstemmed Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title_short Angiogenin Secretion From Hepatoma Cells Activates Hepatic Stellate Cells To Amplify A Self-Sustained Cycle Promoting Liver Cancer
title_sort angiogenin secretion from hepatoma cells activates hepatic stellate cells to amplify a self-sustained cycle promoting liver cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300499/
https://www.ncbi.nlm.nih.gov/pubmed/25604905
http://dx.doi.org/10.1038/srep07916
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