MicroRNA-31-5p enhances the Warburg effect via targeting FIH
MicroRNA-31-5p enhances the Warburg effect via targeting FIH
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MicroRNA-31-5p 通过靶向 FIH 增强 Warburg 效应
DOI：
10.1096/fj.201800803r
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发表时间：
2019-01-01
期刊：
影响因子：
4.8
通讯作者：
Yan, Daoguang
中科院分区：
文献类型：
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作者：
Zhu, Biying;Cao, Xiuye;Yan, Daoguang
在包括肺癌在内的许多人类恶性肿瘤中已经观察到miR-31的表达增强，并且这种microRNA调节肿瘤发生的几个方面。然而，miR-31- 5 p在能量代谢中的作用仍然难以捉摸。在此，我们证实H1299和A549两种肺癌细胞系依赖有氧糖酵解作为ATP的主要来源。抑制miR-31- 5 p导致糖酵解和ATP产生减少，而miR-31- 5 p过表达则增加它们。缺氧诱导因子1（HIF-1）上调糖酵解酶的表达，HIF-1抑制剂（FIH）抑制HIF-1活性。由于FIH是miR-31- 5 p的直接靶点，因此抑制miR-31- 5 p导致FIH表达增强和HIF-1信号转导抑制，而过表达miR-31- 5 p具有相反的作用。通过这种机制，miR-31- 5 p上调有氧糖酵解基因并维持能量稳态。为了进一步验证miR-31- 5 p在糖酵解调节中的机制，我们发现FIH的过表达或敲低分别挽救了miR-31- 5 p或miR-31- 5 p抑制剂对HIF激活及其靶基因表达的影响。最后，通过A549细胞异种移植小鼠模型，我们证明了miR-31- 5 p通过增强糖酵解促进细胞增殖。总之，该研究揭示了miR-31- 5 p通过直接靶向FIH促进瓦尔堡效应。Zhu，B.，Cao，X.，张伟，Pan，G.，Yi，Q.，钟伟，Yan，黑腹叶蝉D. MicroRNA-31- 5 p通过靶向FIH增强瓦尔堡效应。
The enhanced expression of miR-31 has been observed in many human malignancies including lung cancer, and this microRNA regulates several aspects of oncogenesis. However, the role of miR-31-5p in energy metabolism remains elusive. Here, we confirm that H1299 and A549 cells, 2 lung cancer cell lines, relay on aerobic glycolysis as main source of ATP. Inhibition of miR-31-5p leads to decreased glycolysis and ATP production, while miR-31-5p overexpression increases them. Hypoxia inducible factor 1 (HIF-1) up-regulates the expression of glycolytic enzymes, and the HIF-1 inhibitor (FIH) inhibits HIF-1 activity. Because FIH is a direct target of miR-31-5p, inhibition of miR-31-5p results in enhanced FIH expression and suppression of HIF-1 signaling, while overexpression of miR-31-5p has the opposite effects. Via this mechanism, miR-31-5p up-regulates aerobic glycolytic genes and maintains energy homeostasis. To further validate the mechanism of miR-31-5p in glycolysis regulation, we show that overexpression or knockdown of FIH rescued the effects of miR-31-5p or miR-31-5p inhibitor on HIF activation and its target gene expression, respectively. Finally, by means of an A549 cell xenograft mouse model, we demonstrate that the miR-31-5p promotes cell proliferation via enhancing glycolysis. In summary, this study reveals that miR-31-5p promotes the Warburg effect via direct targeting of FIH.Zhu, B., Cao, X., Zhang, W., Pan, G., Yi, Q., Zhong, W., Yan, D. MicroRNA-31-5p enhances the Warburg effect via targeting FIH.