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.
Highlights
Hepatocellular carcinoma (HCC) is the second-deadliest malignancy worldwide[1]
We demonstrate that G6PD levels are altered in liver cancer patients from The Cancer Genome Atlas, its mRNA levels increase in conjunction with rise tumor grade, and its levels negatively correlate with the expression of miR-122 and miR-1, a previously reported regulator of G6PD33,34
We found that G6PD mRNA levels are significantly upregulated in primary tumors from human HCC patients (P-value = 1.082346 × 10−40) when compared to benign tissue (Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) is the second-deadliest malignancy worldwide[1]. Liver tumorigenesis is a multi-step process typically arising from persistent liver damage caused by an underlying liver disease such as alcohol consumption, HCV/HBV viral infection, or metabolic syndrome[2]. Several groups including ours demonstrated that miR-122, a highly conserved liver-specific miRNA expressed in vertebrates[15], is a novel tumor suppressor in HCC16–18. This small (21–23 nt) non-coding RNA regulates gene expression post-transcriptionally by mediating Argonaute binding at the target RNA sites complementary to the miR-122 seed sequence, causing decay of target message[19]. We demonstrate that G6PD levels are altered in liver cancer patients from The Cancer Genome Atlas (http://cancergenome.nih.gov/), its mRNA levels increase in conjunction with rise tumor grade, and its levels negatively correlate with the expression of miR-122 and miR-1, a previously reported regulator of G6PD33,34. To the best of our knowledge, these data demonstrate for the first time that miR-122 regulates G6PD levels in HCC cells, and that loss of expression of miR-1 and miR-122 in primary HCCs may contribute to the increased G6PD activity thereby promoting tumor growth
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