IL-6/NOS2 inflammatory signals regulate MMP-9 and MMP-2 activity and disease outcome in nasopharyngeal carcinoma patients

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 MMPs activation and their possible correlation with (NO)• production. We observed a significant increase in IL-6 and nitrites (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, nitrites 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.

The Acute Phase Reaction and Its Prognostic Impact in Patients with Head and Neck Squamous Cell Carcinoma: Single Biomarkers Including C-Reactive Protein Versus Biomarker Profiles

“…When analyzing our overall data, we observed an association between good prognosis and HPV positivity, whereas adverse prognosis was associated with increasing both CRP levels and WBC counts. These are expected associations that have been described in previous studies [ 9 , 21 , 22 , 23 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 78 ] and therefore suggest that our patient cohort is representative. Furthermore, histopathological features like tumor lymphocyte density predict prognosis both in HPV-negative and HPV-positive oropharyngeal cancer patients [ 79 ].…”

“…Several previous studies have shown that both increased systemic CRP levels [ 8 , 47 , 48 , 49 , 50 , 51 , 52 ] and IL6 levels [ 9 , 21 , 22 , 23 , 53 , 54 , 55 , 56 , 57 ] are associated with an adverse prognosis in HNSCC. IL6 can function as a driver of the acute phase reaction, i.e., increased CRP levels can at least partly be due to an IL6 effect [ 1 , 26 ].…”

“…Systemic inflammatory responses, including the systemic levels of acute phase cytokines, have a prognostic impact in several cancers, including HNSCC [ 9 , 10 , 21 , 22 , 23 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. However, the acute phase reaction is an example of how several cytokines (including IL6 family and IL1 subfamily members as well as TNFα) form an interacting network [ 1 ].…”

AIMP2-DX2 Promotes the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells

“…Matrix metalloproteinases (MMPs) play an important role in the process [ 30 ]. MMP-2 and -9 have been reported to be related with the metastasis of NPC [ 31 , 32 ]. Consistently, the mRNA and protein expression levels of MMP-2/9 were upregulated in NPC cells ( Figure 2 ).…”

Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma

“…304 Besides, IL-6 is able to reduce cell adherence toward laminin and stimulates the expression of MMP-2 and MMP-9, leading to metastasis of NPC. [305][306][307] It is hoped that the emergence of targeted therapies against CSCs and EMT might bring about clinical benefits. However, continued study is still imperative in order to attain the goal of understanding the molecular expression profile together with the characteristics of signal pathways in CSCs.…”