MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency

Abstract

// Louise Y. Fong 1,2 , Cristian Taccioli 3 , Ruiyan Jing 1 , Karl J. Smalley 2 , Hansjuerg Alder 4 , Yubao Jiang 1 , Paolo Fadda 4 , John L. Farber 1 and Carlo M. Croce 4 1 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA 2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 3 Animal Medicine, Production and Health Department, University of Padua, Padua, Italy 4 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Correspondence to: Louise Y. Fong, email: // Keywords : microRNA expression profiling, esophageal squamous cell carcinoma, dietary zinc deficiency dose-response, miR-223, miR-21 Received : December 16, 2015 Accepted : February 08, 2016 Published : February 21, 2016 Abstract Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC), and marginal ZD is prevalent in humans. In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC. Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a). On exposure to an environmental carcinogen, ~16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) ( P ≤ 0.05), but lower than marked-ZD rats (68%) ( P < 0.001). Importantly, the high ESCC, marked-ZD esophagus had a 15-microRNA signature, resembling the human ESCC miRNAome, with miR-223, miR-21, and miR-31 as the top-up-regulated species. This signature discriminated it from the low ESCC, moderate/mild-ZD esophagus, with a 2-microRNA signature (miR-31, miR-223). Additionally, Fbxw7, Pdcd4, and Stk40 (tumor-suppressor targets of miR-223, -21, and -31) were downregulated in marked-ZD cohort. Bioinformatics analysis predicted functional relationships of the 3 tumor-suppressors with other cancer-related genes. Thus, microRNA dysregulation and ESCC progression depend on the extent of dietary Zn deficiency. Our findings suggest that even moderate ZD may promote esophageal cancer and dietary Zn has preventive properties against ESCC. Additionally, the deficiency-associated miR-223, miR-21, and miR-31 may be useful therapeutic targets in ESCC.