IFNAR1 is a predictor for overall survival in colorectal cancer and its mRNA expression correlated with IRF7 but not TLR9

Abstract

Toll-like receptor (TLR) 9 plays a role in intestinal inflammation that, in turn, is related to the tumorigenesis of colorectal cancer. Nuclear factor κB (NFκB), and interferon regulatory factor (IRF) 5 and IRF7 can be activated by TLR9 and induce the production of proinflammatory cytokines and type I interferon, respectively. This study investigated the mRNA expressions of TLR9 and its downstream signaling molecules in both the tumor and the normal tissues of colorectal cancer. Eighty-four subjects with colorectal cancer were consecutively recruited at a community-based hospital, and the mRNA expression of TLR9, NFκB, IRF5, IRF7, interleukin 6 (IL6), and interferon α/β/ω receptor 1 (IFNAR1) in the tumor and normal tissue were determined by real-time reverse transcription polymerase chain reaction using TaqMan FAM-labeled MGB probes (Life Technologies, Carlsbad, CA). The tumor had higher percentages of detection of TLR9, IFNAR1, and IL6 mRNA expressions than normal tissue. The absence of detectable TLR9 mRNA expression was associated with an absence of significance in the correlation between IL6 and NFκB or IRF5, but not that between IRF7 and IFNAR1 in both the tumor and the normal tissues. An absence of detectable IFNAR1 mRNA expression in the tumor (hazard ratio: 3.77; 95% confidence interval: 1.22-11.60) and advanced stage (stages III and IV, 7.86; 1.76-35.40) were significant predictors for overall survival. IFNAR1 is a predictor for overall survival and mRNA expression is correlated to IRF7, but not TLR9 in colorectal cancer. The results cast doubt on the usefulness of TLR9 agonist in treating colorectal cancer.

FIGURE 1

Phi correlation coefficients of mRNA detectability between molecules of the TLR9/NFκB/IRF5/IL6 (in light gray) and TLR9/IRF7/IFNAR1 (in open rectangle) pathways. A large font-size number denotes a correlation with a P value <0.05. Significant positive correlations between the detectability of TLR9 and IRF5 or IL6, and that of IRF7 and IFNAR1 were seen in the tumor but not in the normal tissue. No significant correlation between the detectability of TLR9 and IRF7 was found in both the tumor and the normal tissues. IFNAR1 = interferon α/β/ω receptor 1, IL = interleukin, IRF = interferon regulatory factor, NFκB = nuclear factor κB, TLR9 = Toll-like receptor.

FIGURE 2

Spearman correlation coefficients of detectable mRNA levels between molecules of the TLR9/NFκB/IRF5/IL6 (in light gray) and TLR9/IRF7/IFNAR1 (in open rectangle) pathways. A large font-size number denotes a correlation with a P value <0.05. Bivariate scatterplots are shown in the left lower half of each plot. The absence of detectable TLR9 mRNA expression was associated with an absence of significance in the correlation between IL6 and NFκB or IRF5, but not that between IRF7 and IFNAR1 in both the tumor and the normal tissues. IFNAR1 = interferon α/β/ω receptor 1, IL = interleukin, IRF = interferon regulatory factor, NFκB = nuclear factor κB, TLR9 = Toll-like receptor 9.