Abstract
BackgroundNicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) not only can promote cancer progression, but also they have recently emerged as mediators of the mucosal immune system. However, the roles and clinical relevance of the collective or individual NADPH oxidase (NOX) family genes in cervical cancer have not been studied.MethodsWe investigated the clinical significance of the NOX family genes using data from 307 patients with cervical cancer obtained from The Cancer Genome Atlas. Bioinformatics and experimental analyses were performed to examine NOX family genes in cervical cancer patients.ResultsDual Oxidase1 (DUOX1) and Dual Oxidase 2 (DUOX2) mRNA levels were upregulated 57.9- and 67.5-fold, respectively, in cervical cancer patients. The protein expression of DUOX1, DUOX2, and NOX2 also identified in cervical squamous cell carcinoma tissues. Especially, DUOX1 and DUOX2 mRNA levels were significantly increased in patients infected with human papillomavirus (HPV) 16. Moreover, high DUOX1 mRNA levels were significantly associated with both favorable overall survival and disease-free survival in cervical cancer patients. High NOX2 mRNA levels was significantly associated with favorable overall survival. Gene set enrichment analyses revealed that high DUOX1 and NOX2 expression was significantly correlated with the enrichment of immune pathways related to interferon (IFN)-alpha, IFN-gamma, and natural killer (NK) cell signaling. Cell-type identification by estimating relative subsets of known RNA transcript analyses indicated that the fraction of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, was elevated in patients with high DUOX1 expression.ConclusionsDUOX1 and NOX2 expression are associated with mucosal immunity activated in cervical squamous cell carcinoma and predicts a favorable prognosis in cervical cancer patients.
Highlights
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) can promote cancer progression, and they have recently emerged as mediators of the mucosal immune system
Dual Oxidase1 (DUOX1) and NOX2 expression are associated with mucosal immunity activated in cervical squamous cell carcinoma and predicts a favorable prognosis in cervical cancer patients
Gene Expression Profiling Interactive Analysis (GEPIA; http://gepia.cancer-pku.cn/) was utilized to compare mRNA expression between cervical cancer patients based on data from The Cancer Genome Atlas (TCGA) database and 13 normal controls based on data from The Genotype-Tissue Expression (GTEx) Project from the Broad Institute of MIT and Harvard
Summary
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) can promote cancer progression, and they have recently emerged as mediators of the mucosal immune system. The roles and clinical relevance of the collective or individual NADPH oxidase (NOX) family genes in cervical cancer have not been studied. The NADPH oxidase (NOX) family, the major family of enzymes that catalyze reactive oxygen species (ROS) production, comprises seven members: NOX1–5, dual oxidase (DUOX) 1, and DUOX2 [4]. Oxidative innate immune defense mechanism mediated by NADPH oxidase family members has been emerged, especially, DUOX plays an important role in host mucosal immunity by producing hydrogen peroxide [7,8,9]. The immunologic effect of DUOX in the uterine cervical mucosa, which provides the first line of defense to HPV invasion, especially in cervical cancer, has not yet been investigated
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