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Sci Rep. 2018 Jun 14;8(1):9105. doi: 10.1038/s41598-018-27358-5.

The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase (G6PD) expression in hepatocellular cancer.

Author information

1
Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.
2
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
3
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA.
4
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA. samson.jacob@osumc.edu.
5
Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. tasneem.motiwala@osumc.edu.
6
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. tasneem.motiwala@osumc.edu.
7
Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA. kalpana.ghoshal@osumc.edu.
8
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. kalpana.ghoshal@osumc.edu.

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Thus, a better understanding of molecular aberrations involved in HCC pathogenesis is necessary for developing effective therapy. It is well established that cancer cells metabolize energy sources differently to rapidly generate biomass. Glucose-6-phosphate-dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP), is often activated in human malignancies to generate precursors for nucleotide and lipid synthesis. Here, we determined the clinical significance of G6PD in primary human HCC by analyzing RNA-seq and clinical data in The Cancer Genome Atlas. We found that the upregulation of G6PD correlates with higher tumor grade, increased tumor recurrence, and poor patient survival. Notably, liver-specific miR-122, which is essential for metabolic homeostasis, suppresses G6PD expression by directly interacting with its 3'UTR. Luciferase reporter assay confirmed two conserved functional miR-122 binding sites located in the 3'-UTR of G6PD. Furthermore, we show that ectopic expression of miR-122 and miR-1, a known regulator of G6PD expression coordinately repress G6PD expression in HCC cells. These miRNAs also reduced G6PD activity in HepG2 cells that express relatively high activity of this enzyme. Collectively, this study provides evidence that anti-HCC efficacy of miR122 and miR-1 could be mediated, at least in part, through inhibition of PPP by suppressing the expression of G6PD.

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