ABSTRACT
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-ß, and IL-17A expression levels, concomitantly to NF-κB 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-ß 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.
ABSTRACT
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.
ABSTRACT
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.
