Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identifi...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/52506 |
| Acceso en línea: | http://hdl.handle.net/10810/52506 |
| Access Level: | acceso abierto |
| Palabra clave: | hepatocellular-carcinoma cells sorafenib resistance multikinase inhibitor drug-resistance cancer apoptosis expression puma RAF/MEK/ERK micrornas |
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| dc.title.none.fl_str_mv |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| title |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| spellingShingle |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity Fernández Tussy, Pablo hepatocellular-carcinoma cells sorafenib resistance multikinase inhibitor drug-resistance cancer apoptosis expression puma RAF/MEK/ERK micrornas |
| title_short |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| title_full |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| title_fullStr |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| title_full_unstemmed |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| title_sort |
Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity |
| dc.creator.none.fl_str_mv |
Fernández Tussy, Pablo Rodríguez Agudo, Rubén Fernández Ramos, David Barbier Torres, Lucía Zubiete Franco, Imanol López de Davalillo, Sergio Herráez Aguilar, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofía Simón Espinosa, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia McCain, Misti V. Perugorria Montiel, María Jesús Mabe Alvarez, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix, Loreto Sapena, Victor Anguita Castillo, Juan de Dios Lu, Shelly C. Mato, José M. Bañales Asurmendi, Jesús María Villa, Erica Reeves, Helen L. Bruix, Jordi Reig, María Marín, José J. G. Cardoso Delgado, Teresa de Jesús Martínez Chantar, María Luz |
| author |
Fernández Tussy, Pablo |
| author_facet |
Fernández Tussy, Pablo Rodríguez Agudo, Rubén Fernández Ramos, David Barbier Torres, Lucía Zubiete Franco, Imanol López de Davalillo, Sergio Herráez Aguilar, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofía Simón Espinosa, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia McCain, Misti V. Perugorria Montiel, María Jesús Mabe Alvarez, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix, Loreto Sapena, Victor Anguita Castillo, Juan de Dios Lu, Shelly C. Mato, José M. Bañales Asurmendi, Jesús María Villa, Erica Reeves, Helen L. Bruix, Jordi Reig, María Marín, José J. G. Cardoso Delgado, Teresa de Jesús Martínez Chantar, María Luz |
| author_role |
author |
| author2 |
Rodríguez Agudo, Rubén Fernández Ramos, David Barbier Torres, Lucía Zubiete Franco, Imanol López de Davalillo, Sergio Herráez Aguilar, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofía Simón Espinosa, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia McCain, Misti V. Perugorria Montiel, María Jesús Mabe Alvarez, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix, Loreto Sapena, Victor Anguita Castillo, Juan de Dios Lu, Shelly C. Mato, José M. Bañales Asurmendi, Jesús María Villa, Erica Reeves, Helen L. Bruix, Jordi Reig, María Marín, José J. G. Cardoso Delgado, Teresa de Jesús Martínez Chantar, María Luz |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
hepatocellular-carcinoma cells sorafenib resistance multikinase inhibitor drug-resistance cancer apoptosis expression puma RAF/MEK/ERK micrornas |
| topic |
hepatocellular-carcinoma cells sorafenib resistance multikinase inhibitor drug-resistance cancer apoptosis expression puma RAF/MEK/ERK micrornas |
| description |
Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n=16 and n=20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n=100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n=16) and in an additional cohort of tumor/non-tumor paired samples (n=20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10810/52506 |
| url |
http://hdl.handle.net/10810/52506 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
info:eu-repo/grantAgreement/MINECO/SAF2017-87301-R/ info:eu-repo/grantAgreement/MINECO/SAF2014-52097-R/ info:eu-repo/grantAgreement/MINECO/RTI2018-096759-A100/ info:eu-repo/grantAgreement/MINECO/SAF2016-75197-R/ info:eu-repo/grantAgreement/MINECO/SAF2015-64149-R/ https://www-nature-com.ehu.idm.oclc.org/articles/s41419-021-03827-0 |
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info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/3.0/es/ This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) Atribución 3.0 España |
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openAccess |
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http://creativecommons.org/licenses/by/3.0/es/ This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) Atribución 3.0 España |
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application/pdf |
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Springer Nature |
| publisher.none.fl_str_mv |
Springer Nature |
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reponame:Addi. Archivo Digital para la Docencia y la Investigación instname:Universidad del País Vasco |
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Universidad del País Vasco |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial ActivityFernández Tussy, PabloRodríguez Agudo, RubénFernández Ramos, DavidBarbier Torres, LucíaZubiete Franco, ImanolLópez de Davalillo, SergioHerráez Aguilar, ElisaGoikoetxea Usandizaga, NaroaLachiondo Ortega, SofíaSimón Espinosa, JorgeLopitz Otsoa, FernandoGutiérrez de Juan, VirginiaMcCain, Misti V.Perugorria Montiel, María JesúsMabe Alvarez, JonNavasa, NicolásRodrigues, Cecilia M. P.Fabregat, IsabelBoix, LoretoSapena, VictorAnguita Castillo, Juan de DiosLu, Shelly C.Mato, José M.Bañales Asurmendi, Jesús MaríaVilla, EricaReeves, Helen L.Bruix, JordiReig, MaríaMarín, José J. G.Cardoso Delgado, Teresa de JesúsMartínez Chantar, María Luzhepatocellular-carcinoma cellssorafenib resistancemultikinase inhibitordrug-resistancecancerapoptosisexpressionpumaRAF/MEK/ERKmicrornasDysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n=16 and n=20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n=100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n=16) and in an additional cohort of tumor/non-tumor paired samples (n=20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.This work was supported by grants from NIH (US Department of Health and Human services) R01CA172086 (to S.C.L., J.M.M. and M.L.M.-C.) and P01CA233452 (to S.C.L.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), MINECO: SAF2017-87301-R, SAF2014-52097-R, RTI2018-096759-A100, SAF2016-75197-R and SAF2015-64149-R, integrated in the Plan Estatal de Investigacion Cientifica y Tecnica e Innovacion 2017-2020 cofounded by FEDER funds/Development Fund-a way to build Europe (to M.L.M.-C., J.M.M., T.C.D., J.J.G.M., and I.F., respectively), Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain: PI16/00598 and PI19/00819 (to J.J.G.M.), PI15/01132 and PI18/01075 (to J.M.B.), PI14/00399 and PI17/00022 (to M.J.P.), PI18/0358 (to M.R.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014 and BIO15/CA/016/BD (to M.L.M.-C and J.M.B., respectively); Mitotherapeutix (to M.L.M.-C), Consejeri ' a de Educacio ' n, Junta de Castilla y Leo ' n: SA063P17 (J.J.G.M.), Asociacion Espanola Contra el Cancer (T.C. D, P.F.-T., and M.L.M-C), Basque Government Postdoctoral Program (P.F.-T.), Daniel Alagille award from EASL (to T.C.D.), Asociacion Espanola contra el Cancer, Canceres raros (M.L.M.-C., J.M.B., and J.J.G.M.), La Caixa Foundation (to M.L.M.-C. and J.M.B.), Ayudas Fundacion BBVA a equipos de Investigacion Cientifica 2018 (to M.L.M.-C.), Fondo Europeo de Desarrollo Regional' (FEDER) (to J.M.B.); CIBERehd, Spain (to J.M.B.); IKERBASQUE, Basque foundation for Science, Spain (to J.M.B.), Department of Health of the Basque Country (2017111010) (to J.M.B.), Euskadi RIS3 (2019222054, 2020333010) (to J.M.B.); Department of Industry of the Basque Country (J.M.B.: Elkartek: KK-2020/00008) (to J.M.B.), Ayudas para apoyar grupos de investigacion del sistema Universitario Vasco IT971, Instituto de Salud Carlos III PI18/00768 (J.B.), AECC PI044031 (J.B.), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement 2014 SGR 605 (J.B.), WCR (AICR) 16-0026 (J.B.), Programma di ricerca Regione-Universita 2007-2009 and 2011-2012, Regione EmiliaRomagna (E.V.)Springer Nature202120212021info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/52506reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/SAF2017-87301-R/info:eu-repo/grantAgreement/MINECO/SAF2014-52097-R/info:eu-repo/grantAgreement/MINECO/RTI2018-096759-A100/info:eu-repo/grantAgreement/MINECO/SAF2016-75197-R/info:eu-repo/grantAgreement/MINECO/SAF2015-64149-R/https://www-nature-com.ehu.idm.oclc.org/articles/s41419-021-03827-0info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)Atribución 3.0 Españaoai:addi.ehu.eus:10810/525062026-06-18T09:23:17Z |
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15,300719 |