This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine down-regulated IL-2 by 9% (p=0.04), while celecoxib down-regulated IL-7 by 11% (p=0.006) and up-regulated IL-13 by 17% (p=0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall (OR=1.47, p=0.03) and among those with mild dysplasia at t0 (OR=2.53 p=0.001). An increase in IL-2 tertile from baseline to t10 was also non-significantly associated with worsening dysplasia for all participants (OR=1.32 p=0.098), and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR=2.0 p=0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR=2.52 p=0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, while celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10 month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect on reducing levels of IL-2.

Background

Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma (ESCC), and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia (HGD), and who did or did not have a family history (FH) of upper gastrointestinal cancer (UGI Ca).

Methods

147 samples were evaluated, including 23 (16%) from patients with HGD and 48 (33%) from patients without DYS who heated their homes with coal, without a chimney (a “high” indoor air pollution group), and 27 (18%) from patients with HGD and 49 (33%) from patients without DYS who did not heat their homes at all (a “low” indoor air pollution group). Nearly half (64 (44%)) had a FH of UGI Ca. RNA was extracted and Quantitative-PCR analysis was performed.

Results

AhR gene expression was detectable in 85 (58%) of the samples, and was more than 9-fold higher in those with a FH of UGI Ca (median expression (IQR) -1964 (-18000, -610) versus -18000 (-18000, -1036) Wilcoxon P = 0.02). Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression, all P-values ≥0.1).

Conclusion

AhR expression was higher in patients with a FH of UGI Ca. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer.