Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation.

Epidemiological studies in high-incidence areas of esophageal cancer in China suggest that environmental carcinogen N-nitrosomethylbenzylamine (NMBA) and riboflavin (RBF) deficiency may be the main risk factors for esophageal cancer. However, it is not clear that the combination induces cancer. Here, experiment (Exp) 1 evaluated the effects of NMBA and RBF deficiency individually or in combination on esophageal tumorigenesis. Male F344 rats were randomly assigned to 4 groups into a 2 (no NMBA vs. NMBA) × 2 (normal RBF vs. RBF-deficient) factorial design, including normal RBF (6 mg/kg, R ₆ ), RBF-deficient (0 mg/kg, R ₀ ), normal RBF combined with NMBA (R ₆ N), and RBF-deficient combined with NMBA (R ₀ N) groups. The Exp 2 explored the effects of RBF deficiency at different doses combined with NMBA (0.6 mg/kg, R _0.6 N; 0.06 mg/kg, R _0.06 N) on esophageal tumorigenesis. Results showed that R ₀ N enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 53.3%, P = 0.06), including carcinoma in situ , whereas R ₆ N mainly induced the occurrence of esophageal benign hyperplasia (38.9%) and EIN (16.7%). RBF deficiency promotes EIN in a dose-dependent manner, and R _0.06 N significantly increases the incidence of EIN (57.9%, P < 0.05). Gene expression profiling demonstrated that inflammatory cytokines were highly expressed in R ₀ N EIN tissues, whereas R ₆ N EIN tissues had a proliferation and differentiation gene signature (fold-change > 1.5). Furthermore, RBF deficiency aggravated oxidative DNA damage (8-OHdG) and double-strand breaks (γH2AX) ( P < 0.05). Our results suggest that RBF deficiency causes chronic inflammation-associated genomic instability contributes to NMBA-induced esophageal tumorigenesis.
Competing Interests: None.
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