miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

Abstract

Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3'-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.

MicroRNA-124 suppresses proliferation and glycolysis in non–small cell lung cancer cells by targeting AKT–GLUT1/HKII

“…4,5 The AKT pathway and hypoxiainducible factor 1 (HIF-1) are major signaling cascade that regulates glucose metabolism as well as controls cellular growth. 6,7 They could enhance glucose transporter gene expression, increase phosphofructokinase activity, and stimulate the glucose to lactate metabolic pathway, 8,9 AKT mainly enhances hexokinase II (HKII) gene expression, thus promoting glucose capture. 10 MicroRNAs (miRNAs) are single-stranded, small noncoding RNAs with 18-25 nucleotides in length.…”

The interplay between HIF-1α and noncoding RNAs in cancer

“…The stability of HIF-1α is a critical factor in its action on relevant gene expression, and WD repeat and SOCS box containing 1 (WSB1) has been reported to enhance the HIF-1α protein stability derived from the abnormally low expression of miR-592 in hepatocellular carcinoma cells with enhanced glycolysis and proliferation [144]. In osteosarcoma cells, which have a high energy demand but low ATP-generating efficiency, increasing miR-543 targets the 3'-UTR of protein arginine methyltransferase 9 (PRMT9) to decrease PRMT9-induced HIF-1α instability; thereafter, elevated HIF-1α boosts glycolysis and proliferation of osteosarcoma cells [145].…”

“…In pancreatic cancer, the expression of miR-646 [181] and miR-548 [67] is correlated with clinicopathological indicators such as TNM stage and overall survival (OS), and hypoxia-induced lncRNA NUTF2P3-001 overexpression also indicates advanced TNM stage and shorter survival time of patients [88]. Both Low expression of miR-592 [144] and high expression of miR-130b [184] can bring about poorer OS in hepatocellular carcinoma patients. For gastric cancer, it has been demonstrated that miR-421 regulated by HIF-1α not only causes longer OS, but also can shorten the time to relapse of patients [185], and lncRNA BC005927 induced by hypoxia is also frequently upregulated in gastric cancer samples, showing adverse effects on a series of prognostic parameters, such as TNM stage, lymph node metastasis, and survival time [81].…”

Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma

“…This evidence suggests that hypoxia-induced PIM1 is important for the mitochondrial-glycolytic metabolism shift in HCC. Jia et al (2016) reported that miR-592 was downregulated in HCC specimens. These authors showed that overexpression of miR-592 reduced HIF-1a, glycolytic metabolism, and HCC growth.…”