Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation.
Am J Cancer Res. 2019 ;9(11):2469-2481. Epub 2019 Nov 1. PMID: 31815047
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 NMBANMBA)× 2 (normal RBFRBF-deficient) factorial design, including normal RBF (6 mg/kg, R), RBF-deficient (0 mg/kg, R), normal RBF combined with NMBA (RN), and RBF-deficient combined with NMBA (RN) groups. The Exp 2 explored the effects of RBF deficiency at different doses combined with NMBA (0.6 mg/kg, RN; 0.06 mg/kg, RN) on esophageal tumorigenesis. Results showed that RN enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 53.3%,= 0.06), including carcinoma, whereas RN mainly induced the occurrence of esophageal benign hyperplasia (38.9%) and EIN (16.7%). RBF deficiency promotes EIN in a dose-dependent manner, and RN significantly increases the incidence of EIN (57.9%,<0.05). Gene expression profiling demonstrated that inflammatory cytokines were highly expressed in RN EIN tissues, whereas RN 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) (<0.05). Our results suggest that RBF deficiency causes chronic inflammation-associated genomic instability contributes to NMBA-induced esophageal tumorigenesis.