Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-β-induced epithelial to amoeboid transition.
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ICR Authors
Authors
López-Luque, J
Bertran, E
Crosas-Molist, E
Maiques, O
Malfettone, A
Caja, L
Serrano, T
Ramos, E
Sanz-Moreno, V
Fabregat, I
Bertran, E
Crosas-Molist, E
Maiques, O
Malfettone, A
Caja, L
Serrano, T
Ramos, E
Sanz-Moreno, V
Fabregat, I
Document Type
Journal Article
Date
2019-11-01
Date Accepted
2019-08-22
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.
Citation
Cancer Letters, 2019, 464 pp. 15 - 24
Source Title
Cancer Letters
Publisher
ELSEVIER IRELAND LTD
ISSN
0304-3835
eISSN
1872-7980