Abstract
The Warburg effect is a metabolic hallmark of cancer. Tumor cells rapidly adjust their energy source to glycolysis in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch remains incompletely understood. Here, we show that hypoxia potently induces the down-regulation of miR-125a expression in hepatocellular carcinoma (HCC) cells and tumors. Furthermore, we demonstrate that miR-125a could decrease the production of lactate, the uptake of glucose, and the levels of ATP and reactive oxygen species (ROS) in HCC cells. We investigated the molecular mechanism through which miR-125a inhibits HCC glycolysis and identified hexokinase II (HK2) as a direct target gene of miR-125a. Finally, we revealed that the miR-125a/HK2 axis is functionally important for regulating glycolysis of HCC cell and progression of cancer in vitro and in vivo. In summary, our findings demonstrate for the first time that hypoxia-down-regulated miR-125a regulated HCC glycolysis and carcinogenesis by targeting hexokinase HK2, a key glycolytic enzyme for the Warburg effect, and add a new dimension to hypoxia-mediated regulation of cancer metabolism.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and the incidence of hepatocellular carcinoma (HCC) is expected to increase worldwide[1]
Hexokinase 2 (HK2) is the major isozyme that is abundantly expressed in a variety of cancers and contributes to aerobic glycolysis, and it is reported as a pivotal player in the Warburg effect and is proposed as a metabolic target for cancer therapeutic development[9, 10]
RT-qPCR and in situ hybridization results clearly showing that miR-125a was consistently down-regulated in HCC tumor tissues compared to the corresponding background tissues (Fig. 1c and d)
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and the incidence of HCC is expected to increase worldwide[1]. The Warburg effect, where by cellular energy production is driven by glycolysis even in the face of oxygen levels that are sufficient to support oxidative phosphorylation, is a core metabolic hallmark of cancer[3]. We found for the first time that the down-regulation of miR-125a is crucial for the glycolysis-promoting effect of hypoxia in human HCC cells and tumors. We focused on the functional significance and regulatory mechanisms of the miR125a/HK2 axis in the regulation of the Warburg effect and tumor growth in vitro and in vivo. These results provide new insights into the role of the miR-125a/HK2 axis in the glycolytic switch of HCC and add a new dimension to hypoxia-mediated regulation of cancer metabolism
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