Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression

Cancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual...

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Autores: Rani, Bhavna, Malfettone, Andrea, Dituri, Francesco, Soukupova, Jitka, Lupo, Luigi, Mancarella, Serena, Fabregat Romero, Isabel, Giannelli, Gianluigi
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
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:2445/123991
Acceso en línea:https://hdl.handle.net/2445/123991
Access Level:acceso abierto
Palabra clave:Càncer de fetge
Cèl·lules mare
Fenotip
Liver cancer
Stem cells
Phenotype
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spelling Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expressionRani, BhavnaMalfettone, AndreaDituri, FrancescoSoukupova, JitkaLupo, LuigiMancarella, SerenaFabregat Romero, IsabelGiannelli, GianluigiCàncer de fetgeCèl·lules mareFenotipLiver cancerStem cellsPhenotypeCancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual patients. While sorafenib is currently the only approved drug for first-line treatment of advanced stage HCC, its role in modulating the CSC niche is estimated to be small. By contrast, transforming growth factor (TGF)-beta pathway seems to influence the CSC and thus may impact hallmarks of HCC, such as liver fibrosis, cirrhosis, and tumor progression. Therefore, blocking this pathway may offer an appealing and druggable target. In our study, we have used galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-beta receptor I (TGF beta I/ALK5) activation, currently under clinical investigation in HCC patients. Because the drug resistance is mainly mediated by CSCs, we tested the effects of galunisertib on stemness phenotype in HCC cells to determine whether TGF-beta signaling modulates CSC niche and drug resistance. Galunisertib modulated the expression of stemness-related genes only in the invasive (HLE and HLF) HCC cells inducing a decreased expression of CD44 and THY1. Furthermore, galunisertib also reduced the stemness-related functions of invasive HCC cells decreasing the formation of colonies, liver spheroids and invasive growth ability. Interestingly, CD44 loss of function mimicked the galunisertib effects on HCC stemness-related functions. Galunisertib treatment also reduced the expression of stemness-related genes in ex vivo human HCC specimens. Our observations are the first evidence that galunisertib effectiveness overcomes stemness-derived aggressiveness via decreased expression CD44 and THY1.Nature Publishing Group2018201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion12 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/123991Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))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/10.1038/s41419-018-0384-5Cell Death & Disease, 2018-03-07, Vol. 9:373https://doi.org/10.1038/s41419-018-0384-5info:eu-repo/grantAgreement/EC/FP7/316549cc-by (c) Rani, Bhavna et al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1239912026-05-29T05:05:01Z
dc.title.none.fl_str_mv Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
title Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
spellingShingle Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
Rani, Bhavna
Càncer de fetge
Cèl·lules mare
Fenotip
Liver cancer
Stem cells
Phenotype
title_short Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
title_full Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
title_fullStr Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
title_full_unstemmed Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
title_sort Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression
dc.creator.none.fl_str_mv Rani, Bhavna
Malfettone, Andrea
Dituri, Francesco
Soukupova, Jitka
Lupo, Luigi
Mancarella, Serena
Fabregat Romero, Isabel
Giannelli, Gianluigi
author Rani, Bhavna
author_facet Rani, Bhavna
Malfettone, Andrea
Dituri, Francesco
Soukupova, Jitka
Lupo, Luigi
Mancarella, Serena
Fabregat Romero, Isabel
Giannelli, Gianluigi
author_role author
author2 Malfettone, Andrea
Dituri, Francesco
Soukupova, Jitka
Lupo, Luigi
Mancarella, Serena
Fabregat Romero, Isabel
Giannelli, Gianluigi
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de fetge
Cèl·lules mare
Fenotip
Liver cancer
Stem cells
Phenotype
topic Càncer de fetge
Cèl·lules mare
Fenotip
Liver cancer
Stem cells
Phenotype
description Cancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual patients. While sorafenib is currently the only approved drug for first-line treatment of advanced stage HCC, its role in modulating the CSC niche is estimated to be small. By contrast, transforming growth factor (TGF)-beta pathway seems to influence the CSC and thus may impact hallmarks of HCC, such as liver fibrosis, cirrhosis, and tumor progression. Therefore, blocking this pathway may offer an appealing and druggable target. In our study, we have used galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-beta receptor I (TGF beta I/ALK5) activation, currently under clinical investigation in HCC patients. Because the drug resistance is mainly mediated by CSCs, we tested the effects of galunisertib on stemness phenotype in HCC cells to determine whether TGF-beta signaling modulates CSC niche and drug resistance. Galunisertib modulated the expression of stemness-related genes only in the invasive (HLE and HLF) HCC cells inducing a decreased expression of CD44 and THY1. Furthermore, galunisertib also reduced the stemness-related functions of invasive HCC cells decreasing the formation of colonies, liver spheroids and invasive growth ability. Interestingly, CD44 loss of function mimicked the galunisertib effects on HCC stemness-related functions. Galunisertib treatment also reduced the expression of stemness-related genes in ex vivo human HCC specimens. Our observations are the first evidence that galunisertib effectiveness overcomes stemness-derived aggressiveness via decreased expression CD44 and THY1.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
2018
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/2445/123991
url https://hdl.handle.net/2445/123991
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/10.1038/s41419-018-0384-5
Cell Death & Disease, 2018-03-07, Vol. 9:373
https://doi.org/10.1038/s41419-018-0384-5
info:eu-repo/grantAgreement/EC/FP7/316549
dc.rights.none.fl_str_mv cc-by (c) Rani, Bhavna et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Rani, Bhavna et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
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
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score 15,811543

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