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Bourouba M.,University of Science and Technology Houari Boumediene | Bourouba M.,Boston University | Zergoun A.-A.,University of Science and Technology Houari Boumediene | Maffei J.S.,Boston University | And 6 more authors.
Cytokine | Year: 2015

Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine which mediates via nitric oxide (NO) several carcinogenic processes. Increasing evidences suggest that NO promotes inflammation induced growth of nasopharyngeal carcinoma (NPC). In patients, TNFα synthesis associates with poor survival. To explore the effect of the cytokine on NO production and NOS2 dependent NPC growth, NO2- (nitrite) producing cells in patients were analyzed in vitro. We observed that patients' monocytes/macrophages (Mo/Ma) and primary tumor biopsies synthesized significant amounts of NO2-. Interestingly, tumor explants derived NO2- levels were more important in elderly patients in comparison with juveniles. Endogenous TNFα neutralization with an anti-TNFα monoclonal antibody (mAb) successfully inhibited NO2- synthesis by blood mononuclear cells and tumor explants. Recombinant TNFα (rTNFα) enhanced NO2- synthesis and C666-1 NPC cell proliferation. NOS2 selective inhibition (1400W) and TNFα antagonization with an anti-TNFα mAb potently inhibited rTNFα induced C666-1 proliferation and NO2- production. Importantly, primary tumors treated with the anti-TNFα mAb also displayed reduced proliferation index (Ki67). Altogether, our results define monocytes/macrophages and the primary tumor as major sources of circulating NO2- in NPC patients and support the idea that antibody dependent inhibition of the TNFα/NOS2 pathway may alter NPC tumor growth. © 2015 Elsevier Ltd. Source

Zergoun A.-A.,University of Science and Technology Houari Boumediene | Zebboudj A.,University of Science and Technology Houari Boumediene | Sellam S.L.,University of Science and Technology Houari Boumediene | Kariche N.,University of Science and Technology Houari Boumediene | And 9 more authors.
Tumor Biology | Year: 2015

The role of nitric oxide (NO)· in the development of the metastatic properties of nasopharyngeal carcinoma (NPC) is not fully understood. Previous studies proposed that interleukin-6 (IL-6) would act as regulator of matrix metalloprotease activation in NPC. Recently, we showed that (NO)· was a critical mediator of tumor growth in patients. The aim of this study was to determine the implication of IL-6 in the progression of NPC pathology via metalloprotease (MMP) activation and their possible correlation with (NO)· production. We observed a significant increase in IL-6 and nitrite (NO2 −) synthesis in patients (n = 17) as well as a strong expression of IL-6 and nitric oxide synthase 2 (NOS2) in the analyzed tumors (n = 8). In patients’ plasma, a negative correlation associated IL-6 with circulating nitrites (r = −0.33). A negative correlation associated the H-scores of these signals in the tumors (r = −0.47). In patients’ plasma, nitrite synthesis was positively associated with MMP-9 activation (r = 0.45), pro-MMP-2 expression (r = 0.37), and negatively correlated with MMP-2 activation (r = −0.51). High nitrite levels was associated with better recurrence-free survival (RFS) (p = 0.02). Overall, our results suggest that the IL-6/NOS2 inflammatory signals are involved in the regulation of MMP-9- and MMP-2-dependent metastatic activity and that high circulating nitrite levels in NPC patients may constitute a prognostic predictor for survival. © 2015 International Society of Oncology and BioMarkers (ISOBM) Source

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