Background:High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations.Methods:We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan–Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used.Results:High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03–2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59–2.76; P<0.001) over and above NLR.Conclusions:High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.

ABSTRACT. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of targeted mRNAs. An increasing amount of evidence indicates that miRNAs play important role in cancer pathogenesis, apoptosis, proliferation, and differentiation as oncogenes or tumor suppressors. Recently, miRNA-199a has been shown to be involved in many human cancers, although the role of miRNA-199a-3p in gastric cancer has not yet been evaluated. In the present study, the expression of miRNA-199a-3p was found to be significantly downregulated in human gastric cancer tissues and cells. miRNA-199a-3p induced anti-proliferation effects on human gastric cancer cells. Furthermore, using quantitative RT-PCR (real-time polymerase chain reaction) and luciferase reporter assays, mTOR was identified as a direct target gene of miRNA-199a-3p that is downregulated by it. In conclusion, our findings suggest that miRNA-199a-3p is associated with human gastric cancer through its ability to decrease cancer cell proliferation and target the mTOR signaling pathway, and, therefore, may provide a novel Role of miRNA-199a-3p in gastric carcinomas therapeutic target for the treatment of human gastric cancer.