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Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-beta-induced epithelial to amoeboid transition
Bellvitge Biomed Res Inst IDIBELL, Oncobell Program, TGP B, Barcelona, Spain;Bellvitge Biomed Res Inst IDIBELL, Oncobell Program, Canc Grp, Barcelona, Spain;Inst Salud Carlos III, Oncol Program, CIBEREHD, Natl Biomed Res Inst Liver & Gastrointestinal Dis, Madrid, Spain.
Bellvitge Biomed Res Inst IDIBELL, Oncobell Program, TGP B, Barcelona, Spain;Bellvitge Biomed Res Inst IDIBELL, Oncobell Program, Canc Grp, Barcelona, Spain;Inst Salud Carlos III, Oncol Program, CIBEREHD, Natl Biomed Res Inst Liver & Gastrointestinal Dis, Madrid, Spain.
Queen Mary Univ London, Barts Canc Inst, Canc Res UK Ctr Excellence, John Vane Sci Bldg Charterhouse Sq, London EC1M 6BQ, England.
Queen Mary Univ London, Barts Canc Inst, Canc Res UK Ctr Excellence, John Vane Sci Bldg Charterhouse Sq, London EC1M 6BQ, England.
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2019 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 464, no Nov, p. 15-24Article in journal (Refereed) Published
Abstract [en]

The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-beta) 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-beta is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-beta 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-beta-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-beta upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFBI or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-beta-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-beta 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.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD , 2019. Vol. 464, no Nov, p. 15-24
Keywords [en]
Liver, Migration, Adhesion, Matrix, Myosin II
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-395562DOI: 10.1016/j.canlet.2019.08.011ISI: 000487572200003PubMedID: 31465839OAI: oai:DiVA.org:uu-395562DiVA, id: diva2:1362670
Funder
EU, FP7, Seventh Framework Programme, PITN-GA-2012-316549Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved

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