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

• Published in: American journal of cancer research 2019-01, Vol.9 (11), p.2469-2481
• Main Authors: Pan, Feng, Chen, Ye, He, Jian-Zhong, Long, Lin, Chen, Yang, Luo, Hong-Jun, Xu, Yi-Wei, Pang, Xiao-Xiao, Yang, Qian, Wang, Juan-Juan, Xu, Xiu-E, Wang, Shao-Hong, Li, En-Min, Xu, Li-Yan
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 2156-6976; 2156-6976

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 NMBA) × 2 (normal RBF RBF-deficient) factorial design, including normal RBF (6 mg/kg, R ), RBF-deficient (0 mg/kg, R ), normal RBF combined with NMBA (R N), and RBF-deficient combined with NMBA (R N) groups. The Exp 2 explored the effects of RBF deficiency at different doses combined with NMBA (0.6 mg/kg, R N; 0.06 mg/kg, R N) on esophageal tumorigenesis. Results showed that R N enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 53.3%, = 0.06), including carcinoma , whereas R 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 N significantly increases the incidence of EIN (57.9%, < 0.05). Gene expression profiling demonstrated that inflammatory cytokines were highly expressed in R N EIN tissues, whereas R 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) ( < 0.05). Our results suggest that RBF deficiency causes chronic inflammation-associated genomic instability contributes to NMBA-induced esophageal tumorigenesis.