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EnglishIntroduction: 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.
| Titolo: | EXPRESSION OF COX-2 IN HUMAN BREAST CANCER CELLS AS A CRITICAL DETERMINANT OF EPITHELIAL-MESENCHYMAL TRANSITION AND INVASIVENESS |
| Autori Riconosciuti: | |
| Autori: | C. BOCCA; M. IEVOLELLA; R. AUTELLI; M. MOTTA; L. MOSSO; B. TORCHIO; F. BOZZO; S. CANNITO; C. PATERNOSTRO; S. COLOMBATTO; M. PAROLA; A. MIGLIETTA |
| Data di pubblicazione: | 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. |
| Volume: | 18 |
| Fascicolo: | 2 |
| Pagina iniziale: | 121 |
| Pagina finale: | 135 |
| Digital Object Identifier (DOI): | 10.1517/14728222.2014.860447 |
| Parole Chiave: | COX-2, EMT, invasiveness, hypoxia, MCF-7 cells, MDA-MB-231 cells, ROS |
| Rivista: | EXPERT OPINION ON THERAPEUTIC TARGETS |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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| File | Descrizione | Tipologia | Licenza | |
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| Revised Manuscript_4aperto (1).pdf | POSTPRINT (VERSIONE FINALE DELL’AUTORE) | Accesso riservato | Open Access Visualizza/Apri | |
| Exp Op Ther Targets 2013-1.pdf | PDF editoriale | PDF EDITORIALE | Utenti riconosciuti Richiedi una copia |
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