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

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.

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…Besides the upregulated genes in the glycolysis pathway, G6PD and TKT in the pentose phosphate pathway were also consistently upregulated, which predicted worse survival. This is consistent with previous reported functions of these two genes associated with aggressiveness of the disease and drug resistance in other cancer types [54][55][56][57][58]. Most of the genes involved in glycogen metabolism such as GYS2, UGP2, and AGL had down-regulated expression when compared to normal tissues.…”

Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets

“…miR-122 can function as a tumor suppressor by suppressing HCC growth, invasion, migration, angiogenesis and by increasing HCC apoptosis and cell cycle arrest (52). miRNA-122 targets multiple genes, including BCL9, Bcl-w, NDRG3, cyclin G1, ADAM17, ADAM10, G6PD, and pituitary tumortransforming gene 1 (PTTG1) binding factor (PBF), all of which have been implicated in tumor development (53)(54)(55)(56)(57)(58)(59)(60). Other miRNAs such as miRNA-21 function as oncogenes by stimulating HCC growth, invasion, and migration (23,61,62).…”

Extracellular Vesicles Derived Human-miRNAs Modulate the Immune System in Type 1 Diabetes

“…Using NGS sequencing and comparison of blood plasma EVs profiles of healthy controls, nT1D individuals with an active beta-cell destruction, and 10yT1D participants with non-detectable beta-cell activity or autoimmunity process, we characterized differentially expressed EVs miRNA in T1D (Figures 2A-C). The most prominently overexpressed miRNAs in the nT1D cohort was hsa-miR-122-5p, previously associated with liver pathology (Hu et al, 2012), metabolism regulation (Willeit et al, 2017;Barajas et al, 2018), and T1D (Åkerman et al, 2018). Elevated hsa-miR-192-5p and hsa-miR-193b-5p in T1D are reported as markers of prediabetes in the adult population (Párrizas et al, 2015).…”