Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia
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Louise Y. Fong1,2,3, Ruiyan Jing1, Karl J. Smalley2, Cristian Taccioli4, Johannes Fahrmann5, Dinesh K. Barupal5, Hansjuerg Alder7, John L. Farber1, Oliver Fiehn5,6 and Carlo M. Croce7
1 Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
2 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
3 Center for Molecular Carcinogenesis, Thomas Jefferson University, Philadelphia, PA, USA
4 Animal Medicine, Production and Health Department, University of Padua, Padua, Italy
5 University of California, Davis, West Coast Metabolomics Center, Davis, CA, USA
6 Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
7 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
Louise Y. Fong, email:
Carlo M. Croce, email:
Keywords: metabolomic profiling, transcriptomics and microRNA profiling integration, esophageal neoplasia, dietary zinc-deficiency, miR-143 - Hk2 - glucose signaling
Received: April 27, 2017 Accepted: May 29, 2017 Published: June 09, 2017
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 Zn-deficient 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.
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