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Title: Downregulation of epidermal growth factor receptor in hepatocellular carcinoma facilitates transforming growth factor-β-induced epithelial to amoeboid transition
Author: López Luque, Judit
Bertran Rodríguez, Esther
Crosas Molist, Eva
Maiques, Oscar
Malfettone, Andrea
Caja Puigsubirà, Laia
Serrano Piñol, M. Teresa
Ramos Rubio, Emilio
Sanz Moreno, Victoria
Fabregat Romero, Isabel
Keywords: Càncer
Càncer de fetge
Factors de creixement
Liver cancer
Growth factors
Issue Date: 1-Nov-2019
Publisher: Elsevier B.V.
Abstract: The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.
Note: Reproducció del document publicat a:
It is part of: Cancer Letters, 2019, vol. 1 , num. 464, p. 15-24
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ISSN: 0304-3835
Appears in Collections:Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

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