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: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| 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:2445/178840 |
| Acceso en línea: | https://hdl.handle.net/2445/178840 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer de fetge Apoptosi Marcadors bioquímics Liver cancer Apoptosis Biochemical markers |
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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, SergioHerraez, ElisaGoikoetxea Usandizaga, NaroaLachiondo Ortega, SofiaSimón, JorgeLopitz Otsoa, FernandoGutiérrez de Juan, VirginiaMccain, Misti V.Perugorria, Maria J.Mabe, JonNavasa, NicolásRodrigues, Cecilia M. P.Fabregat, IsabelBoix i Ferrero, LoretoSapena, VictorAnguita, JuanLu, Shelly C.Mato, José M.Banales, Jesus M.Villa, EricaReeves, Helen L.Bruix Tudó, JordiReig, MaríaMarin, Jose J. G.Delgado, Teresa C.Martínez Chantar, Maria LuzCàncer de fetgeApoptosiMarcadors bioquímicsLiver cancerApoptosisBiochemical markersDysregulation 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.Springer Science and Business Media LLC2021202120212021info:eu-repo/semantics/article16 p.application/pdfhttps://hdl.handle.net/2445/178840Articles 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/s41419-021-03827-0Cell Death & Disease, 2021, vol. 12, num. 555https://doi.org/10.1038/s41419-021-03827-0cc by (c) Fernández Tussy, Pablo et al., 2021http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1788402026-05-29T05:05:01Z |
| 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 Càncer de fetge Apoptosi Marcadors bioquímics Liver cancer Apoptosis Biochemical markers |
| 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 Herraez, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofia Simón, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia Mccain, Misti V. Perugorria, Maria J. Mabe, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix i Ferrero, Loreto Sapena, Victor Anguita, Juan Lu, Shelly C. Mato, José M. Banales, Jesus M. Villa, Erica Reeves, Helen L. Bruix Tudó, Jordi Reig, María Marin, Jose J. G. Delgado, Teresa C. Martínez Chantar, Maria 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 Herraez, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofia Simón, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia Mccain, Misti V. Perugorria, Maria J. Mabe, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix i Ferrero, Loreto Sapena, Victor Anguita, Juan Lu, Shelly C. Mato, José M. Banales, Jesus M. Villa, Erica Reeves, Helen L. Bruix Tudó, Jordi Reig, María Marin, Jose J. G. Delgado, Teresa C. Martínez Chantar, Maria Luz |
| author_role |
author |
| author2 |
Rodríguez Agudo, Rubén Fernández Ramos, David Barbier Torres, Lucía Zubiete Franco, Imanol López de Davalillo, Sergio Herraez, Elisa Goikoetxea Usandizaga, Naroa Lachiondo Ortega, Sofia Simón, Jorge Lopitz Otsoa, Fernando Gutiérrez de Juan, Virginia Mccain, Misti V. Perugorria, Maria J. Mabe, Jon Navasa, Nicolás Rodrigues, Cecilia M. P. Fabregat, Isabel Boix i Ferrero, Loreto Sapena, Victor Anguita, Juan Lu, Shelly C. Mato, José M. Banales, Jesus M. Villa, Erica Reeves, Helen L. Bruix Tudó, Jordi Reig, María Marin, Jose J. G. Delgado, Teresa C. Martínez Chantar, Maria 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 |
Càncer de fetge Apoptosi Marcadors bioquímics Liver cancer Apoptosis Biochemical markers |
| topic |
Càncer de fetge Apoptosi Marcadors bioquímics Liver cancer Apoptosis Biochemical markers |
| 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 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/178840 |
| url |
https://hdl.handle.net/2445/178840 |
| 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/s41419-021-03827-0 Cell Death & Disease, 2021, vol. 12, num. 555 https://doi.org/10.1038/s41419-021-03827-0 |
| dc.rights.none.fl_str_mv |
cc by (c) Fernández Tussy, Pablo et al., 2021 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc by (c) Fernández Tussy, Pablo et al., 2021 http://creativecommons.org/licenses/by/3.0/es/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
16 p. application/pdf |
| dc.publisher.none.fl_str_mv |
Springer Science and Business Media LLC |
| publisher.none.fl_str_mv |
Springer Science and Business Media LLC |
| 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) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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1869405509921013760 |
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15,198674 |