title: MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency.
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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.|Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Fong
authors.affiliation: Animal Medicine, Production and Health Department, University of Padua, Padua, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Jing
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Smalley
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fadda
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Farber
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000172:deficiency*
chemical_list: D035683:MicroRNAs; D015032:Zinc
keywords: dietary zinc deficiency dose-response; esophageal squamous cell carcinoma; miR-21; miR-223; microRNA expression profiling