State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Advanced Institute of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, Jiangsu, 210093, China.
Department of Radiotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, 210009, China.
Sci Rep. 2017 Jun 8;7(1):3089. doi: 10.1038/s41598-017-03407-3.
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.
瓦博格效应是癌症的一种代谢特征。肿瘤细胞迅速调整其能量来源为糖酵解，以在缺氧环境中有效地增殖，但这种转变的机制仍不完全清楚。在这里，我们表明缺氧强烈诱导肝癌 (HCC) 细胞和肿瘤中 miR-125a 表达的下调。此外，我们证明 miR-125a 可以降低 HCC 细胞中乳酸的产生、葡萄糖的摄取以及 ATP 和活性氧 (ROS) 的水平。我们通过研究 miR-125a 抑制 HCC 糖酵解的分子机制，鉴定出己糖激酶 2 (HK2) 是 miR-125a 的直接靶基因。最后，我们揭示了 miR-125a/HK2 轴在体外和体内调节 HCC 细胞糖酵解和癌症进展方面具有重要功能。总之，我们的研究结果首次表明，缺氧下调的 miR-125a 通过靶向己糖激酶 HK2 调节 HCC 糖酵解和致癌作用，这是瓦博格效应的关键糖酵解酶，为缺氧介导的癌症代谢调节增添了新的维度。
