MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency
| Autor: | Karl J. Smalley, Paolo Fadda, John L. Farber, Cristian Taccioli, Hansjuerg Alder, Yubao Jiang, Louise Y.Y. Fong, Carlo M. Croce, Ruiyan Jing |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Dietary zinc deficiency dose-response Esophageal squamous cell carcinoma MicroRNA expression profiling MiR-21 MiR-223 Oncology Esophageal Neoplasms chemistry.chemical_element Zinc Rats Sprague-Dawley Mice Random Allocation 03 medical and health sciences 0302 clinical medicine mir-223 microRNA medicine Animals Humans Esophagus 2. Zero hunger business.industry Esophageal cancer Hyperplasia medicine.disease digestive system diseases 3. Good health MicroRNAs 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Carcinoma Squamous Cell Zinc deficiency Cancer research business Priority Research Paper |
| Zdroj: | Oncotarget |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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