miR-23a: A Key Metabolic Regulator in Hepatocellular Carcinoma
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Biomedical Engineering Honors Theses; 2014
Considerable efforts have been made in elucidation of the mechanisms that drive cancer metabolism towards high levels of anaerobic glycolysis.1 We have demonstrated that the expression and activity of key enzymes within the gluconeogenesis pathway are drastically reduced in human and mouse hepatocellular carcinoma (HCC), which is at least partially due to a significant upregulation of microRNA-23a (miR-23a).2 We have further shown that the messenger RNAs (mRNA) coding for two vital gluconeogenic enzymes, PGC-1α (the major transcription coactivator for key gluconeogeneic enzymes) and glucose-6-phosphatase (G6PC), are direct targets of miR-23a.2 This was the first report that demonstrated the role of a specific miRNA in regulation of gluconeogenesis in HCC.2 Although these findings have established a key role for miR-23a in gluconeogenesis, its potential for the regulation of other metabolic pathways requires further investigation. To explore this possibility, we utilized Phenotype MircoArrayTM technology to determine the effects of miR-23a expression on the cellular metabolism of nearly one hundred different metabolites. This analysis revealed a significant role of miR-23a in the inhibition of citrate metabolism. mRNA coding for Aconitase (ACO1), a key enzyme involved in the citric acid cycle, has a potential binding site for miR-23a in its 3’ untranslated region (UTR). We confirmed the attenuation of ACO1 by miR-23a through real-time RT-PCR and 3’ UTR luciferase reporter assays. These results indicate that significant up-regulation of miR-23a may play an essential role in the shift of cancer cell metabolism towards high levels of anaerobic glycolysis and nucleotide synthesis through the accumulation of glucose-6-phosphate.
Academic Major: Biomedical Engineering
Pelotonia Undergraduate Research Fellowship
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