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...

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Detalles Bibliográficos
Autores: 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
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
Descripción
Sumario: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.

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