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Title: Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity
Author: 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
Keywords: Càncer de fetge
Marcadors bioquímics
Liver cancer
Biochemical markers
Issue Date: 28-May-2021
Publisher: Springer Science and Business Media LLC
Abstract: 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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It is part of: Cell Death & Disease, 2021, vol. 12, num. 555
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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