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J Hepatol. 2019 Sep 25. pii: S0168-8278(19)30549-5. doi: 10.1016/j.jhep.2019.09.012. [Epub ahead of print]

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

Author information

1
Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain. Electronic address: dcaballero@idibell.cat.
2
Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain.
3
TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain.
4
Dept. Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain.
5
Oncology Data Analytics Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBER Epidemiología y Salud Pública (CIBERESP), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
6
Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain; Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain.
7
Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain; Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain.
8
Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain. Electronic address: ifabregat@idibell.cat.

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-β (TGF-β) 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-β-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-β 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-β 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-β-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-β 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-β pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-β-targeted therapy.

LAY SUMMARY:

Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Cltc), altering the cellular response to TGF-β 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-β.

KEYWORDS:

Anti-TGF-beta therapy; Cancer biology; Clathrin; EGFR; HCC; Hepatocyte; Intracellular traffic; Liver; TGF-β

PMID:
31562907
DOI:
10.1016/j.jhep.2019.09.012
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