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oai:docta.ucm.es:20.500.14352/1068522024-07-18T23:54:04Zcom_20.500.14352_14col_20.500.14352_15

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer Caballero-Díaz, Daniel Bertran, Esther Peñuelas-Haro, Irene Moreno-Càceres, Joaquim Malfettone, Andrea López-Luque, Judit Addante, Annalisa Herrera González, Blanca María Sánchez Muñoz, Aranzazu Alay, Ania Solé, Xavier Serrano, Teresa Ramos, Emilio Fabregat Romero, María Isabel 577.1 577.2 Clathrin HCC TGF-b EGFR Liver Hepatocyte Intracellular traffic Cancer biology Anti-TGF-beta therapy Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida Background & Aims: Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-b (TGFb) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-b-induced signalling in liver cells and its relevance in liver cancer. Methods: Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-b and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGFB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC). Results: Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-b phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-b-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-b signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. Conclusions: This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-b pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-b-targeted therapy. Lay summary: Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Cltc), altering the cellular response to TGF-b in favour of anti-apoptotic/ pro-tumorigenic signals. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-b. Ministerio de Ciencia, Innovación y Universidades (España) Instituto de Salud Carlos III European Commission-ERC Depto. de Bioquímica y Biología Molecular Fac. de Farmacia TRUE pub 2024-07-18T10:20:18Z 2024-07-18T10:20:18Z 2020-01 journal article AM https://hdl.handle.net/20.500.14352/106852 0168-8278 10.1016/j.jhep.2019.09.012 eng info:eu-repo/grantAgreement/MINECO//SAF2015-64149-R/ES/NUEVOS CONOCIMIENTOS SOBRE EL PAPEL DE LA NADPH OXIDASA NOX4 EN HEPATOCARCINOGENESIS. RELEVANCIA EN LA VIAS DE SEÑALIZACION DEL TGF-BETA Y DEL RECEPTOR DEL EGF/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094079-B-I00/ES/NUEVAS APROXIMACIONES EXPERIMENTALES PARA ANALIZAR EL PAPEL DE LA NADPH OXIDASA NOX4 EN REGENERACION Y CANCER HEPATICOS. RELACION CON LA VIA DEL TGF-BETA/ info:eu-repo/grantAgreement/MINECO//SAF2015-69145-R/ES/NUEVAS PERSPECTIVAS SOBRE LOS MECANISMOS MOLECULARES QUE REGULAN LA EXPANSION Y EL DESTINO DE LAS CELULAS PROGENITORAS HEPATICAS DURANTE LA ENFERMEDAD CRONICA HEPATICA/ info:eu-repo/grantAgreement/MINECO//BES-2013-064609/ES/BES-2013-064609/ info:eu-repo/grantAgreement/MINECO//BES-2016-0077564/ES/BES-2016-0077564/ info:eu-repo/grantAgreement/EC/FP7/201119/EU PITN-GA-2012-316549 Caballero-Díaz, Daniel, et al. «Clathrin Switches Transforming Growth Factor-β Role to pro-Tumorigenic in Liver Cancer». Journal of Hepatology, vol. 72, n.o 1, enero de 2020, pp. 125-34. DOI.org (Crossref), https://doi.org/10.1016/j.jhep.2019.09.012. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ metadata only access application/pdf