Introduction: Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression. Objectives: We investigated whether changes in COX-2 expression may affect epithelial-to-mesenchymal transition (EMT) and then invasive potential of human breast cancer cells, in relationship with hypoxia. COX-2-null MCF-7 human breast cancer cells, MCF-7 cells transiently expressing COX-2, and COX-2-expressing MDA-MB-231 cells were employed. Results: COX-2 overexpression resulted in down-regulation of E-cadherin and ß-catenin, up-regulation of vimentin, N-cadherin and SNAI1, suggesting EMT occurrence. COX-2-overexpressing MCF-7 cells were also characterized by increased invasiveness and release of matrix-metalloproteinase-9. The above-mentioned characteristics, homologous to those detected in highly invasive MDA-MB-231 cells, were reverted by treatment of COX-2-overexpressing MCF-7 cells with celecoxib, a COX-2 specific inhibitor, partly through the inhibition of COX-2-related intracellular generation of reactive oxygen species. Hypoxia further exacerbated COX-2 expression, EMT changes and invasive ability in both COX-2-overexpressing MCF-7 cells and MDA-MB-231 cells. Finally, immunohistochemistry performed on samples from normal and neoplastic human breast tissues revealed that COX-2-positive malignant cells were also positive for EMT-related antigens, HIF-2α and the oxidative stress marker heme-oxygenase. Conclusions: These findings support the existence of a direct link between COX-2 overexpression, EMT and invasiveness in human breast cancer cells, emphasizing the role of hypoxic microenvironment.

EXPRESSION OF COX-2 IN HUMAN BREAST CANCER CELLS AS A CRITICAL DETERMINANT OF EPITHELIAL-MESENCHYMAL TRANSITION AND INVASIVENESS

BOCCA, Claudia;AUTELLI, Riccardo;BOZZO, FRANCESCA;CANNITO, STEFANIA;PATERNOSTRO, CLAUDIA;COLOMBATTO, Sebastiano;PAROLA, Maurizio;MIGLIETTA, Antonella
2014

Abstract

Introduction: Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression. Objectives: We investigated whether changes in COX-2 expression may affect epithelial-to-mesenchymal transition (EMT) and then invasive potential of human breast cancer cells, in relationship with hypoxia. COX-2-null MCF-7 human breast cancer cells, MCF-7 cells transiently expressing COX-2, and COX-2-expressing MDA-MB-231 cells were employed. Results: COX-2 overexpression resulted in down-regulation of E-cadherin and ß-catenin, up-regulation of vimentin, N-cadherin and SNAI1, suggesting EMT occurrence. COX-2-overexpressing MCF-7 cells were also characterized by increased invasiveness and release of matrix-metalloproteinase-9. The above-mentioned characteristics, homologous to those detected in highly invasive MDA-MB-231 cells, were reverted by treatment of COX-2-overexpressing MCF-7 cells with celecoxib, a COX-2 specific inhibitor, partly through the inhibition of COX-2-related intracellular generation of reactive oxygen species. Hypoxia further exacerbated COX-2 expression, EMT changes and invasive ability in both COX-2-overexpressing MCF-7 cells and MDA-MB-231 cells. Finally, immunohistochemistry performed on samples from normal and neoplastic human breast tissues revealed that COX-2-positive malignant cells were also positive for EMT-related antigens, HIF-2α and the oxidative stress marker heme-oxygenase. Conclusions: These findings support the existence of a direct link between COX-2 overexpression, EMT and invasiveness in human breast cancer cells, emphasizing the role of hypoxic microenvironment.
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COX-2, EMT, invasiveness, hypoxia, MCF-7 cells, MDA-MB-231 cells, ROS
C. BOCCA; M. IEVOLELLA; R. AUTELLI; M. MOTTA; L. MOSSO; B. TORCHIO; F. BOZZO; S. CANNITO; C. PATERNOSTRO; S. COLOMBATTO; M. PAROLA; A. MIGLIETTA
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/139953
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