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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.

SUBMITTER: Fong LY

PROVIDER: S-EPMC4905434 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Fong Louise Y LY Taccioli Cristian C Jing Ruiyan R Smalley Karl J KJ Alder Hansjuerg H Jiang Yubao Y Fadda Paolo P Farber John L JL Croce Carlo M CM

Oncotarget 20160301 10

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 enviro ...[more]

PMID: 26918602

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Project description:BackgroundEsophageal cancer (ESCA) is a heterogeneous cancer with variable outcomes that are challenging to predict. MicroRNA (miR)-1269a is a newly discovered non-coding RNA that shows promising prognostic prediction in other cancers, but its clinical value in ESCA remains unclear.AimTo explore the relationship between miR-1269a and its clinical value and to develop a nomogram to succinctly display this relationship.MethodsWe analyzed the expression of miR-1269a in 125 ESCA tissue samples with complete clinical data and 52 normal tissue samples. We determined the prognostic value of miR-1269a for overall survival (OS) and cancer-specific survival (CSS) and evaluated the association between miR-1269a and clinical variables including tumor location, histologic grade, metastatic stage, and American Joint Committee on Cancer (AJCC) stage using multivariate Cox analysis. Additionally, we developed a nomogram for OS and CSS based on miR-1269a expression using age and AJCC stage and assessed its prognostic performance. Using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes analyses, we predicted the target genes of miR-1269a and analyzed their potential function in caner development.ResultsThe expression of miR-1269a was significantly higher in ESCA patients than healthy controls. Patients with high expression of miR-1269a showed poor prognosis in OS and CSS, suffered increased rates of low differentiation and metastasis, and exhibited tumor stage T3 + T4, positive lymph stage, and AJCC stage III + IV. The area under the receiver operating characteristic curve of miR-1269a was 0.716 for OS and 0.764 for CSS. Multivariate Cox analysis revealed that AJCC stage and miR-1269a were independent factors for OS and CSS. Combing with age, we constructed a nomogram for prognostic prediction. Additionally, our nomogram showed excellent predictive performance for OS and CSS after 3 years and 5 years and was easy to use. Ultimately, the functional analysis suggested that miR-1269a was mostly involved in the PI3K-AKT signaling pathway.ConclusionmiR-1269a can be used as a potential indicator for the prognosis of ESCA patients. We developed an easy-to-use nomogram with excellent ESCA prognostic prediction for clinical use.

Dataset Information

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

Publications

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

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