The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination: NOX4 represses epithelial to amoeboid transition

Eva Crosas Molist, Esther Bertran, Irene Rodriguez Hernandez, Cecilia Herraiz, Gaia Cantelli, Angels Fabra, Victoria Marta Sanz Moreno, Isabel Fabregat

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54 Citations (Scopus)
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Abstract

Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboid
transition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highly
metastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or threedimensional
complex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficient
amoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated with
invasive features. NOX4 is necessary to maintain parenchymal structures, increase cell–cell and cell-to-matrix adhesion, and impair
actomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating with
higher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPase
expression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42
levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worse
prognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing to
tumour aggressiveness.
Original languageEnglish
Number of pages13
JournalOncogene
Publication statusE-pub ahead of print - 12 Dec 2016

Keywords

  • HCC
  • metastasis
  • migration
  • invasion
  • cell adhesion
  • Rho

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