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

TY - JOUR

T1 - The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination

T2 - NOX4 represses epithelial to amoeboid transition

AU - Crosas Molist, Eva

AU - Bertran, Esther

AU - Rodriguez Hernandez, Irene

AU - Herraiz, Cecilia

AU - Cantelli, Gaia

AU - Fabra, Angels

AU - Sanz Moreno, Victoria Marta

AU - Fabregat, Isabel

PY - 2016/12/12

Y1 - 2016/12/12

N2 - Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboidtransition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highlymetastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or threedimensionalcomplex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficientamoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated withinvasive features. NOX4 is necessary to maintain parenchymal structures, increase cell–cell and cell-to-matrix adhesion, and impairactomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating withhigher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPaseexpression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worseprognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing totumour aggressiveness.

AB - Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboidtransition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highlymetastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or threedimensionalcomplex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficientamoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated withinvasive features. NOX4 is necessary to maintain parenchymal structures, increase cell–cell and cell-to-matrix adhesion, and impairactomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating withhigher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPaseexpression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worseprognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing totumour aggressiveness.

KW - HCC

KW - metastasis

KW - migration

KW - invasion

KW - cell adhesion

KW - Rho

M3 - Article

SN - 0950-9232

JO - Oncogene

JF - Oncogene

ER -