Abstract Introduction: Oral squamous cell carcinoma (OSCC) is characterized by extracellular matrix (ECM) remodeling associated to a pro-inflammatory and protumoral metabolic activity that promote invasion and metastatic progression. This study assessed the effect of a triple therapy combining sodium arsenite (NaAsO2), chloroquine (CQ), and dichloroacetate (DCA) on inflammatory signaling and ECM remodeling in a 4-nitroquinoline-1-oxide (4NQO)-induced tongue OSCC mouse model. Methods: Eight-week-old female BALB/c mice were exposed to chemical induction with the carcinogen (100 µg/ml) or treated with placebo (water control) for 16 weeks, then observed for up to 16 additional weeks. At 32 weeks post-treatment, mice were sacrificed, and their tongues were removed. The oral tumor tissues were then cultured for 24 hours in the presence of NaAsO2, CQ, and DCA. Tumor tissues and explants were analyzed for TNF-α, nitric oxide (NO), matrix metalloproteinase-9 (MMP-9), and collagen integrity. Results: 4NQO carcinogenic activity on animal tongues led to a significant development of dysplasia and invasive SCC cases. OSCC explants culture showed in comparison to healthy tissues elevated levels of nitric oxide production, associated with increased expression of the pro-tumoral TNF-α, MMP-9 expression and collagen fiber disorganization were increased in such conditions. Surprisingly whereas NaAsO2 alone amplified inflammatory mediators, its combination with CQ and DCA significantly decreased NO and TNF-α levels. Strikingly this effect led to a significant downregulation of MMP-9, and preserved Type IV collagen architecture. Masson’s trichrome staining revealed a restoration of dense, parallel collagen fibers resembling those found in an ECM architecture observed in low-grade dysplasic tongues in comparison with OSCC. These findings demonstrate that TNF-α/NO-driven MMP-9 activation is a central mechanism of ECM degradation in OSCC, and that a simultaneous modulation of aerobic glycolysis and autophagy may disrupt the metastatic signaling axis involved in extracellular matrix remodeling and metastatic activity in 4nqo-induced oral squamous cell carcinoma. Conclusion: Altogether, our findings show that our combined treatment was able to reprogram the inflammatory process of tumor progression by inhibiting the molecular processes involved in extracellular matrix remodeling and invasion. This combined treatment represents a novel avenue for metabolic-inflammation-targeting strategy for OSCC in particular in view of the limited treatment options and the risk of chemoresistance. Citation Format: Mounia Benbelkacem, Nabila Moulai, Eimen Kais Kadri, Lina Stamboul, Henni Chader, Wahiba Ouhaioune, Mehdi Bourouba. Inhibition of extracellular matrix remodeling and metastatic activity by dichloroacetate and chloroquine in the presence of arsenite in 4nqo-induced oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 439.

Promyelomonocytic leukemia (PML) is a prominent oncosuppressor whose inactivation is involved in the pathogenesis of hematological and epithelial cancers. Here, we report that PML aggregated in nuclear bodies in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. PML aggregation occurred after the fusion of nuclei (karyogamy) within syncytia but before the apoptotic program was activated. The aggregation of PML was detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Using a range of specific inhibitors of PML (the oncogenic PML/RARα fusion product or specific small interfering RNAs), we demonstrated that, in Env-elicited syncytia, PML was required for activating phosphorylation of ataxia telangiectasia mutated (ATM), which colocalized with PML in nuclear bodies, in a molecular complex that also involved topoisomerase IIβ-binding protein 1. PML knockdown thus inhibited the ATM-dependent DNA damage response that culminates in the activation of p53, p53-dependent transcription of pro-apoptotic genes and cell death. Infection of CD4-expressing cells with HIV-1 also induced syncytial apoptosis, which could be suppressed by inhibiting PML. Altogether, these data indicate that PML activation is a critical early event that participates in the apoptotic demise of HIV-1-elicited syncytia.

Oral squamous cell carcinoma (OSCC) is a disabling tumor with poor response to chemotherapy. Here, we sought to explore a new chemotherapeutic approach based on a combined induction of cytotoxic ROS and targeting of autophagy and aerobic glycolysis as central contributors to OSCC carcinogenesis and chemoresistance. To this end, tongue OSCC was generated in BALB/c mice using 4NQO. Treatment of mouse-derived OSSC explants with NaAsO2 resulted in a strong inhibition of MTT activity and Bcl-2 and Ki-67 expression. The addition of chloroquine (CQ) and dichloroacetate (DCA) to arsenite, resulted in additive inhibitory effects on Bcl-2 and Ki-67 expression. Whereas NaAsO2 alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO2-dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO2 combination with CQ and DCA improved the oxidative status balance by boosting anti-oxidative CAT and SOD and controlling pro-oxidant MDA activity. The administration of the combo to 4NQO-mice resulted in a significant survival advantage over the control group (90% vs. 35% survival at week 32, p< 0.02; HR (log-rank) = 0.166, CI 95% 0.03-0.73). This effect was accompanied by a significant increase in mice's mean body weight (p< 0.009). Contrarily to the control, administration of the combo resulted in the absence of progression towards severe dysplasia and OSCC and an overrepresentation of low/mild dysplasia events (100%). Interestingly, signs of hepatocellular and renal toxicity following combo administration were limited in comparison to control. Taken together, these results suggest that NaAsO2 combined with CQ and DCA may constitute an interesting alternative to eliminating chemo-resistant OSSC tumors by inhibiting aerobic glycolysis and autophagy and controlling ROS generation. In vivo, the drugs may provide a survival advantage by inhibiting tumor development.

EDITORIAL article Front. Immunol., 25 January 2023Sec. Cancer Immunity and Immunotherapy Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1122736

Predicting tumor recurrence and death in patients with nasopharyngeal carcinoma (NPC) remains to date challenging. We here analyzed the plasmatic secretomes of NPC untreated and relapsing patients, and explored possible correlations with the clinical and pathological features and survival characteristics of the corresponding patient cohorts, with the aim of identifying novel prognostic biomarkers. This study included 27 controls, 45 untreated NPC and 11 relapsed patients. A set of 14 plasma cytokines were analyzed using Millipore multiplex assay. Nitrites were assessed by Griess method. A comparative analysis of each groups' secretome showed upregulation of IL-8, IL-12p70, IL-10 and IP-10 in untreated patients, and of IL-6, IL-10, MCP-1 and IP-10 in relapsing patients. Nitrites significantly correlated with IL-8 during relapse. Secretomes' network analyses revealed prevalence of high correlations between IL8/IL-17A and IFN-γ/IL12p70 in the control group, between TNF-α/IL-8/IL-6, TNF-α/VEGF/IFN-γ and IL-10/MCP-1 in the untreated group, and between IL-8/IL-6/IL-10, TNF-α/IL-8/IL-6, IL12-p70/VEGF/IL-10/IFN-γ, IL-6/IL-10/IFN-γ and IL-8/IP-10 in the relapse group. IL-12p70, IP-10 and MCP-1 levels respectively associated with gender, age and node metastasis respectively. Recurrence-free survival (RFS) analysis showed that patients presenting High IL-8/Low NO immunological scores presented a combined 80% probability of relapse/death after 53 months (combined log-rank test p = 0.0034; individual p = 0.012 and p = 0.016). Multivariate Cox hazard regression analysis revealed that IL-8 (HR = 7.451; 95% CI [2.398-23.152]; p = 0.001) and treatment type (HR = 0.232; 95% CI 0.072-0.749; p = 0.015) were independent prognostic factors. C&RT decision tree analysis showed that High IL-8/Low NO immunological scores predicted treatment failure in 50% cases starting the 36th month of follow-up (AUC = 1) for all of the studied cases and in 57% cases for patients receiving chemotherapy alone (AUC = 1). Altogether, our results showed that NPC development is accompanied with cytokines deregulation to form specific interaction networks at time of diagnosis and relapse, and demonstrate that High IL-8/Low NO signature may constitute a predictor of poor prognosis which may be useful to improve risk stratification and therapy failure management.

Breast cancer is one of the commonest cancers among Algerian females. Compared to Western populations, the median age of diagnosis of breast cancer is much lower in Algeria. The objective of this study is to explore the expression of several miRNAs reported to be deregulated in breast cancer. The miRNAs miR-21, miR-125b, miR-100, miR-425-5p, miR-200c, miR-183 and miR-182 were studied on tumor and normal adjacent Algerian breast tissues using quantitative reverse transcription real time PCR, and the results were analyzed according to clinical characteristics. Compared to the normal adjacent tissues, miR-21, miR-183, miR-182, miR-425-5p and miR-200c were found to be upregulated while miR-100 and miR-125b were insignificantly deregulated. A positive correlation was noted among miR-183, miR-182 and miR-200c and among miR-425-5p, miR-183, miR-200c and miR-21. Further global miRNA microarray profiling studies can aid in finding ethnic specific miRNA biomarkers in the Algerian breast cancer population.

The upregulation of checkpoint inhibitor PD-L1 expression has recently been associated with nasopharyngeal carcinoma (NPC) resistance to therapy. The mechanism of induction of PD-L1 has also been linked to enhanced aerobic glycolysis promoted by HIF1-α dysregulation and LDH-A activity in cancer. Here, we investigated the effect of the anti-tumoral compound Silibinin on HIF-1α/LDH-A mediated cancer cell metabolism and PD-L1 expression in NPC. Our results demonstrate that exposure to Silibinin potently inhibits tumor growth and promotes a shift from aerobic glycolysis toward oxidative phosphorylation. The EBV + NPC cell line C666-1 and glycolytic human tumor explants treated with Silibinin displayed a reduction in LDH-A activity which consistently associated with a reduction in lactate levels. This effect was accompanied by an increase in intracellular citrate levels in C666-1 cells. Accordingly, expression of HIF-1α, a critical regulator of glycolysis, was down-regulated after treatment. This event associated with a down-regulation in PD-L1. Altogether, our results provide evidence that silibinin can alter PD-L1 expression by interfering with HIF-1α/LDH-A mediated cell metabolism in NPC. These results provide a new perspective for Silibinin use to overcome PD-L1 mediated NPC resistance to therapy.

Laryngeal squamous cell carcinoma (LSCC) is an aggressive malignancy which lacks early predictors of prognosis. Here, we hypothesized that expression and prognostic characterization of the critical mediators of epithelial to mesenchymal transition (EMT) may provide key information in this regard. Linear regression and multiple correspondence analyses were performed on immunohistochemical data obtained from 20 invasive tumors. Principal component and unsupervised hierarchical clustering were used to analyze the dataset patterns associating with LSCC metastatic profile. Survival and death risk assessments were performed using Kaplan–Meier and hazard ratio tests. Data mining analysis using CHAID decision tree and logistic regression analysis was applied to define the predictive value of the risk factors of tumor aggressiveness. Our analyses showed, that in invasive LSCC tumors, cells associating with a mesenchymal profile were likely to exhibit enhanced NOS2, TGF- β , and IL-17A expression levels, concomitantly to NF- κ B nuclear translocation. IHC data deciphering determined that EMT induction was also linked to the enrichment of the tumors with CD68+ populations and IL-10 signal. Strikingly, dataset cluster analysis showed that these signatures could define distinct patterns of invasive tumors, where NOS2 associated with IL-10 expression, and TGF- β and IL-17A signals associated with MMP-9 activation. Decision tree analysis identified IL-17A as a possible predictor of LSCC aggressiveness. Altogether, our results show that distinct immunological patterns would support the acquisition of EMT features in invasive LSCC and suggest that IL-17A may be useful in the early identification of patients “at-risk” of therapeutic failure.

Background: Despite the increasing incidence of laryngeal squamous cell carcinoma (LSCC) in Algeria, scarce information is available on the importance of the preventable etiological factors which may drive the disease. Remarkably, a significant number of cases occur in nonsmoker and nondrinker patients; hence, suggesting that alternative risk factors, like Human papillomavirus (HPV), might be etiologically involved. To gain more insight on the risk factors associated with the disease in the country, we evaluated the etiological fraction of HPV in comparison to tobacco and alcohol intake in LSCC patients. Methods: To evaluate the etiopathologic fraction (EF) for HPV compared to history of tobacco and alcohol in LSCC, HPV DNA presence in 46 invasive and 3 non-invasive formalin-fixed paraffin-embedded laryngeal tumors was screened using the SPF10-DEIA-LiPA25 Assay. Demographic data and information related to exposure to the risk factors were gathered through interviewer-assisted questionnaires. Results: We observed that 40.8% of all LSCC cases were associated with smoking, 40.8% had combined tobacco and alcohol exposure history, and 14.3% did not show prior exposure to either risk factor. 1 out of 3 in-situ carcinoma cases was positive for HPV-6. HPV prevalence was null in the invasive tumors. HPV DNA was detected in 2.38% for all studied cases. 10.2% of LSCC patients did not associate with any of the studied risk factors. Conclusion: Here we show that HPV etiological fraction in LSCC Algerian patients is low and smoking and alcohol remain the principal etiopathologic risk for LSCC burden in Algeria.

We previously showed that in patients, nitric oxide synthase activity (NOS2) promoted nasopharyngeal tumor growth (NPC). Tumor necrosis factor (TNFα) is a pro-inflammatory cytokine which engages nitric oxide (NO∗) in several carcinogenic processes. In NPC patients, TNFα synthesis associates with poor survival. Here, we aimed at determining whether TNFα signaling inhibition could alter NOS2 dependent NPC growth in vitro. For this purpose, TNFα influence on nitrite production and tumor cell proliferation were analyzed. We observed that monocytes/macrophages (Mo/Ma) and primary tumor biopsies, isolated from patients, synthesized significant amounts of nitrites. Endogenous TNFα neutralization with an anti-TNFα monoclonal antibody (mAb) successfully inhibited nitrites synthesis by Mo/Ma and tumor explants. Recombinant TNFα (rTNFα) enhanced nitrites synthesis and C666-1 NPC cells proliferation. Treatment with the NOS2 selective inhibitor (1400 W) and an anti-TNFα mAb potently inhibited rTNFα induced C666-1 proliferation and nitrites synthesis. Strikingly, patients tumors explants treated with the anti-TNFα mAb displayed reduced proliferation as indicated by Ki67 index. Altogether, our results define Mo/Ma and the primary tumor as major sources of circulating NO∗ in NPC patients and support the idea that antibody dependent inhibition of the TNFα/NOS2 inflammatory pathway may alter nasopharyngeal carcinoma tumor growth.

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.

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.

Event Abstract Back to Event Enhanced autophagy follows LMP1 expression disruption in EBV+ P3HR1 cells treated with arsenic trioxide. Abderezak Zebboudj1*, Chafia Touil-Boukoffa1 and Mehdi Bourouba1 1 University of Sciences and Technologies Houari Boumediene (USTHB), FSB, Algeria Introduction : The Epstein Barr Virus (EBV) latency is associated with several malignancies among which nasopharyngeal carcinoma (NPC) and immunocompromised patients lymphoma. Expression and signaling of the major viral oncogene latent membrane protein 1 (LMP1) is essential to the immortalization of NPC cells and in vitro of B lymphocytes. Arsenic trioxide (ATO) treatment was reported to induce apoptosis in NPC cells via LMP1 down-regulation. Conversely, autophagy has been linked to LMP1 expression in B cells and survival. Here, we analyzed the anti-proliferative activity of ATO on P3HR1 EBV+ lymphoblastoid cells and assessed it's effect on apoptosis, autophagy and LMP1 expression. Materials and Methods : LMP1 expressing cells P3HR1 were treated with different concentrations of ATO. Apoptosis was measured by annexin V/PI double staining. DiOC6 labeling was assessed for mitochondrial potential (ΔΨm). Degree of autophagy was assessed based on LC3BI/LC3BII conversion. The anti-proliferative effect of ATO was studied using soft agar clonogenicity test. LMP1 expression and transcription was analyzed by western blot and Q-RT-PCR. Results : Our results show that ATO treatment leads to increased annexin V labeling and loss of mitochondrial potential in P3HR1 cells. We found that apoptosis is accompanied with enhanced autophagic activity as indicated by LC3B profile. Our results also indicate that ATO treatment induces disruption of LMP1 expression after 72H of treatment and inhibition of its transcription. Thus effects were associated with suppression of cells clonogenicity. Conclusion : Our study suggests that ATO cytotoxicity in P3HR1 cells occurs via induction of apoptosis and up-regulation of autophagic activity. These processes may occur as a consequence of LMP1 transcription repression and depletion of cellular LMP1 pools. Taken together, our data suggest that ATO may regulate negatively tumor cells survival by suppressing LMP1 anti-apoptotic signaling and enhancing autophagic cell death. Acknowledgements This work was performed and co-directed in collaboration with Dr Mounira Chelbi- Alix and Dr Sébastien Nisole team "INSERM UMR-S 1124, Université Paris Descartes,Paris, France". We thank Pr Mohamed Seghier "Institut Pasteur d'Algérie" for material and technical support. Keywords: ATO, apoptosis and autophagy, LMP1, ebv, Lymphoma, B-Cell Conference: The First International Congress of Immunology and Molecular Immunopathology (CIMIP2014), Tlemcen, Algeria, 17 Oct - 20 Oct, 2014. Presentation Type: Oral Poster Presentation Topic: Lymphoproliferative disorders Citation: Zebboudj A, Touil-Boukoffa C and Bourouba M (2014). Enhanced autophagy follows LMP1 expression disruption in EBV+ P3HR1 cells treated with arsenic trioxide.. Front. Immunol. Conference Abstract: The First International Congress of Immunology and Molecular Immunopathology (CIMIP2014). doi: 10.3389/conf.fimmu.2014.04.00007 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Sep 2014; Published Online: 01 Dec 2014. * Correspondence: Mr. Abderezak Zebboudj, University of Sciences and Technologies Houari Boumediene (USTHB), FSB, Bab-Ezzouar, Algiers, 16111, Algeria, azebboudj@usthb.dz Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Abderezak Zebboudj Chafia Touil-Boukoffa Mehdi Bourouba Google Abderezak Zebboudj Chafia Touil-Boukoffa Mehdi Bourouba Google Scholar Abderezak Zebboudj Chafia Touil-Boukoffa Mehdi Bourouba PubMed Abderezak Zebboudj Chafia Touil-Boukoffa Mehdi Bourouba Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Epstein-Barr virus (EBV) is associated with several malignancies, including carcinomas, such as nasopharyngeal carcinoma, and lymphomas, such as Burkitt's lymphoma and Hodgkin's lymphoma. The Latent Membrane Protein 1 (LMP1) is the major oncogene protein of EBV as its expression is responsible for the induction of cell transformation, immortalization and proliferation. Arsenic trioxide was shown to induce a cytotoxic effect on nasopharyngeal cancer cells associated with LMP1 down-regulation. However, the effect of arsenic on EBV-associated lymphoproliferative malignancies has been less studied. We investigated the effect of two different arsenical compounds, arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) on the induction of cell death in P3HR1 cells, an Epstein-Barr virus-positive Burkitt lymphoma derived cell line. Both compounds inhibited cell growth and induced cell death. By flow-cytometry and Western blot analysis, we provide evidence that NaAsO2 induced caspase-dependent apoptosis whereas As2O3 triggered autophagic cell death. Furthermore, we show that NaAsO2 treatment led to a dramatic decrease of the expression level of LMP1 and the cellular protein PML. Importantly, this down-regulation was associated with a reactivation of EBV lytic cycle through the induction of immediate-early proteins Zta and Rta. These results are in agreement with a model in which LMP1 maintains EBV in a latent state by stabilizing PML expression. Altogether, our results suggest that NaAsO2 would represent a better therapeutic candidate than As2O3 in EBV-induced B lymphoma for its capacity to promote viral reactivation.

Interleukin-12 (IL-12) plays an essential role in the promotion of pro-inflammatory and antitumoral immunity. IL-12 may exert its effect via nitric oxide, a molecular effector of activated macrophage induced cytotoxicity. We recently described that nasopharyngeal carcinoma development, in Algerian patients, associates with increased NO synthesis. In this study, we aimed to determine if IL-12 up-regulated NOS2 induction participates to this process. Tumor explants, peripheral blood mononuclear cells (PBMC) and Human Monocyte-Derived Macrophages isolated from NPC patients (n = 20) were cultured in presence or absence of anti-IL12 antibody or an iNOS inhibitor (LNMA). The modulatory effect of IL-12 antagonization on nitrite production was measured in cell culture, as an indirect assessment of NO activity. We observed that nitrites concentrations synthesized by patients’ Monocyte-Derived Macrophages cultures were increased in comparison to healthy controls. NPC explants (3 mm3) synthesised micromolar quantities of nitrites. LNMA (3 mM) based iNOS inhibition, potently inhibited nitrite production in all cell cultures. Antibody based antagonization of IL12 signalling potently inhibited NO production in tumours explants and in Monocyte-Derived Macrophages cultures. Interestingly, no massive features of apoptotic demise were observed in IL-12 positive NPC explants or in patients’ PBMC cultures. Our results suggest that IL12 expression by tumour associated cells induces NO production in nasopharyngeal carcinoma tissues, but fail to induce a nitric oxide dependent anti-tumoral activity. Taken together, our results suggest that IL-12 mediated NO production may be used by the tumour to promote its development.

Nasopharyngeal carcinoma (NPC) is thought to arise because of chronic inflammation. The correlation between nitric oxide (NO) production, a biomarker of inflammation and NPC development remains unexplored. To investigate this question, we performed a profile analysis on plasma collected from untreated, treated, remissive, cured and relapsing patients. Nitrites were measured to assess NO activity. We observed that increased nitrites concentrations in untreated and relapsing patients associated with tumor development. Moreover, nitrites levels were similar in remissive, cured and healthy individuals. Altogether, our results suggest that NO might be an interesting blood biomarker to monitor tumor growth in NPC patients.