Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia

Authors

Louise Y. Fong, Thomas Jefferson UniversityFollow
Ruiyan Jing, Thomas Jefferson UniversityFollow
Karl Smalley, Thomas Jefferson UniversityFollow
Cristian Taccioli, University of PaduaFollow
Johannes Fahrmann, University of California, Davis
Dinesh K. Barupal, University of California, Davis
Hansjuerg Alder, The Ohio State UniversityFollow
John L. Farber, Thomas Jefferson UniversityFollow
Oliver Fiehn, University of California, Davis; King Abdulaziz University
Carlo M. Croce, The Ohio State University, ColumbusFollow

Document Type

Article

Publication Date

6-9-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Oncotarget Volume 8, Issue 47, June 2017, Pages 81910-81925

The published version is available at DOI: 10.18632/oncotarget.18434. Copyright © Fong et al.

Abstract

Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P < 0.0001), indicating aerobic glycolysis (the "Warburg effect"), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zndeficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. © Fong et al.

Recommended Citation

Fong, Louise Y.; Jing, Ruiyan; Smalley, Karl; Taccioli, Cristian; Fahrmann, Johannes; Barupal, Dinesh K.; Alder, Hansjuerg; Farber, John L.; Fiehn, Oliver; and Croce, Carlo M., "Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia" (2017). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 222.
https://jdc.jefferson.edu/pacbfp/222

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This work is licensed under a Creative Commons Attribution 3.0 License.