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.