The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis
The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis
复制标题
microRNA-182-PDK4 轴通过调节丙酮酸脱氢酶和脂肪生成来调节肺肿瘤发生。
DOI：
10.1038/onc.2016.265
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发表时间：
2017-02-16
期刊：
影响因子：
8
通讯作者：
Hu, G.
中科院分区：
文献类型：
--
作者：
Li, G.;Li, M.;Hu, G.
重编程代谢是癌症的标志之一。癌症中糖酵解的失调已经被大量研究。然而，在很大程度上仍然不清楚癌细胞中其他代谢过程是如何调节的。在这里，我们发现microRNA-182（miR-182）抑制丙酮酸脱氢酶（PDH）激酶4（PDK 4）并促进肺肿瘤发生。miR-182在人肺腺癌中失调并与PDK 4负相关。miR-182-PDK 4轴通过调节PDH的活性来调节肺癌细胞生长，PDH是丙酮酸流入乙酰辅酶A的守门酶，随后是癌细胞的从头脂肪生成。通过沉默ATP柠檬酸裂合酶（ACLY）和脂肪酸合酶（FATCH）或通过化学抑制剂抑制脂肪生成减少了miR-182-PDK 4在肿瘤生长中的作用。从头脂肪生成的改变也影响活性氧（ROS）的产生和下游JNK信号通路。因此，我们的工作表明miR-182-PDK 4轴是癌细胞代谢的重要调节因子，也是抗肿瘤治疗的潜在靶点。
Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells. Suppression of lipogenesis by silencing ATP citrate lyase (ACLY) and fatty acid synthase (FASN) or by chemical inhibitors diminishes the effects of miR-182-PDK4 in tumor growth. Alteration of de novo lipogenesis also affects reactive oxygen species (ROS) production and the downstream JNK signaling pathway. Hence, our work suggests that the miR-182-PDK4 axis is a crucial regulator of cancer cell metabolism and a potential target for antitumor therapy.