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

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

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Caballero-Diaz J of HEPATOLOGY 2020.pdf (2.15 MB)

Official URL

https://doi.org/10.1016/j.jhep.2019.09.012

Publication date

2020

Authors

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

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URI

https://hdl.handle.net/20.500.14352/106852

Citation

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.

Abstract

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.