Prognostic Value of Inducible Nitric Oxide Synthase (iNOS) in Human Cancer: A Systematic Review and Meta-Analysis

Abstract

Background. Inducible nitric oxide synthase (iNOS) is confirmed to regulate the production of nitric oxide (NO) when cells are exposed to external stimulus. Recent publications revealed that overexpression of iNOS predicted poor clinical outcomes for patients with malignant cancers, e.g., gastric, bladder, and colorectal cancers; however, several studies reported no obvious relationship between iNOS expression and prognosis of solid tumors. The aim of our study was to investigate the pooled effect of the prognostic value of iNOS expression. Materials and Methods. We performed a systematic search of PubMed, Web of Science, and Embase databases up to January 15, 2019. The concerned outcomes of interest included overall survival (OS), cancer-special survival (CSS), and recurrence-free survival (RFS). Results. Fourteen studies with 1,758 patients were included in this meta-analysis, and we reached the conclusion that increased iNOS expression was significantly associated with worse OS (HR: 1.89, 95% CI: 1.57 - 2.28, p ≤ 0.001), worse CSS (HR: 3.13, 95% CI: 1.88 - 5.20, p ≤ 0.001), and worse RFS (HR: 2.16, 95% CI: 1.29 - 3.62, p = 0.003) in solid tumors. Furthermore, the subgroup analysis identified the significant relationship of high iNOS expression with poor OS in gastric cancer. No obvious publication bias was detected by Begg’s tests. Conclusion. In summary, the results drawn in our meta-analysis demonstrated that elevated expression of iNOS had a significant association with poor survival in human cancer. iNOS might serve as a promising predictive biomarker of prognosis in cancer patients, and well-designed prospective studies are further needed to substantiate the prognostic value of iNOS.

iNOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer

“…Therefore, each expression pattern may have distinct, or even opposing, relevance to the tumor biology and clinical behavior of tumors. A recent meta-analysis suggested that iNOS expression has an ominous prognostic impact in solid tumors, but the analysis was based on immunohistochemical data provided by published studies that used different cut-off points of iNOS expression and, furthermore, the analysis did not focus on the distinct patterns of expression within tumors [12]. For example, overexpression of iNOS by tumor-associated macrophages has been linked to a favorable prognosis in breast and lung cancer [13,14].…”

Microarray-based Analysis of Genes, Transcription Factors, and Epigenetic Modifications in Lung Cancer Exposed to Nitric Oxide

“…The expression of NOS has been reported in many cancers, including breast, cervical, head and neck, and lung cancer (29), and the presence of NO in the cancer area has been linked to the aggressiveness of the diseases (12). The expression of inducible nitric oxide synthase (iNOS) in cancer cells as well as the expression of NOS in the environment of cancers have been shown to predict poor survival (30). Molecular explanations on how NO regulates chemotherapeutic resistance as well as attenuates cancer cell response to immune cell-mediated death have been suggested by many researchers (11,31,32).…”

The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors

“…It is well documented that the intrinsic feature of malignant cells required to produce NO, mostly by constitutive expression of iNOS, is related to poor prognosis. Liao et al recently reported a highly significant association between iNOS expression and disease outcome following overall, cause-specific, and disease-free survival [119]. According to results obtained through meta-analysis, all parameters were remarkably worse in patients with solid tumors expressing iNOS.…”