Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia
Autor: | Oliver Fiehn, Johannes F. Fahrmann, Karl J. Smalley, Hansjuerg Alder, Ruiyan Jing, Dinesh Kumar Barupal, Louise Y.Y. Fong, John L. Farber, Carlo M. Croce, Cristian Taccioli |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty MicroRNA Gene Biology miR-143 - Hk2 - glucose signaling Transcriptome 03 medical and health sciences transcriptomics and microRNA profiling integration 0302 clinical medicine microRNA medicine metabolomic profiling Cancer medicine.disease dietary zinc-deficiency Warburg effect 3. Good health Gene expression profiling 030104 developmental biology Oncology Anaerobic glycolysis 030220 oncology & carcinogenesis esophageal neoplasia Cancer cell Cancer research Dietary zinc-deficiency Esophageal neoplasia Metabolomic profiling MiR-143 - Hk2 - glucose signaling Transcriptomics and microRNA profiling integration Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
DOI: | 10.18632/oncotarget.18434 |
Popis: | // Louise Y. Fong 1,2,3 , Ruiyan Jing 1 , Karl J. Smalley 2 , Cristian Taccioli 4 , Johannes Fahrmann 5 , Dinesh K. Barupal 5 , Hansjuerg Alder 7 , John L. Farber 1 , Oliver Fiehn 5,6 and Carlo M. Croce 7 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 Correspondence to: 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 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 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. |
Databáze: | OpenAIRE |
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