Zinc intake, microRNA dysregulation, and esophageal cancer

(ESCC) is a deadly disease with a 5-year survival of only 10% [1]. Because of the absence of early symptoms, ESCC is commonly diagnosed at an advanced stage. Thus, the development of new prevention and therapeutic approaches are urgently needed. Dietary zinc (Zn) deficiency (ZD), a significant public health issue affecting 31% of the global population [2], is associated with an increased risk of ESCC development [3]. Since marginal Zn deficiency is prevalent in humans [4], it was important to learn the effect of mild to moderate Zn deficiency on ESCC etiology. Our previous work, using rat model systems, has advanced understanding of the role of Zn in ESCC carcinogenesis. Zn deficiency promotes ESCC by inducing an inflammatory gene signature with up-regulation of cancer-associated inflammation genes & an oncogenic microRNA (miRNA) signature featuring up-regulation of oncogenic miR-31 [5]. Our recent dose-response study [6] showed that miRNA dysregulation and esophageal cancer development depended on the extent of dietary Zn deficiency. This tumorigenesis study used low doses of the environmental carcinogen N-nitrosomethyl-benzylamine (NMBA) in rats fed diets containing different amounts of Zn (3, 6, 12, or 60 mg Zn/kg) to represent marked-ZD, moderate-ZD, mild-ZD, and Zn-sufficiency in human Zn nutrition. miRNA expression profiling of human tumors has identified signatures associated with staging, progression, prognosis, and response to treatment [7]. We correlated miRNA expression changes with the above noted ZD doses and ZD-associated esophageal tumor outcome by performing miRNA profiling of esophageal mucosa from carcinogen-treated and untreated rats at study endpoint. Marked zinc deficiency (3 mg Zn/kg diet) alone induced a highly proliferative/inflammatory esophagus accompanied by an oncogenic 5-microRNA signature (miR-31,-223,-21,-146b,-146a). Moderate & mild zinc deficiency (6 & 12 mg Zn/kg diet) also induced sustained hyperplasia and inflammation, albeit less pronounced than marked deficiency, with a 2-microRNA signature (miR-31,-146a). The oncomiR miR-21 that was prominently overexpressed (up 4.2 fold) in the highly Editorial hyperplastic marked zinc deficient esophagus, however, was not differentially expressed in the less hyperplastic moderate/mild zinc deficient esophagus, providing evidence that miRNA signatures distinguish the highly hyperplastic esophageal phenotype induced by marked deficiency from the less hyperplastic esophageal phenotype induced by moderate and mild zinc deficiency. With exposure to NMBA, ~16% of moderate/mild-ZD rats developed ESCC, an incidence greater than for Zn-sufficient rats (0%) (P≤0.05) but lower than for marked-ZD rats (68%) (P<0.001) (n=27 rats/cohort). These data show a dose-response relationship between the extent of zinc deficiency and ESCC development …