State Key Laboratory of Molecular Biology, Graduate School of Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
EMBO J. 2012 Apr 18;31(8):1985-98. doi: 10.1038/emboj.2012.45. Epub 2012 Feb 21.
Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is an anomalous characteristic of glucose metabolism in cancer cells. Chronic inflammation is a key promoting factor of tumourigenesis. It remains, however, largely unexplored whether and how pro-tumourigenic inflammation regulates glucose metabolism in cancer cells. Here, we show that pro-inflammatory cytokines promote glycolysis in breast cancer cells, and that the inflammation-induced miR-155 functions as an important mediator in this process. We further show that miR-155 acts to upregulate hexokinase 2 (hk2), through two distinct mechanisms. First, miR-155 promotes hk2 transcription by activation of signal transducer and activator of transcription 3 (STAT3), a transcriptional activator for hk2. Second, via targeting C/EBPβ (a transcriptional activator for mir-143), miR-155 represses mir-143, a negative regulator of hk2, thus resulting in upregulation of hk2 expression at the post-transcriptional level. The miR-155-mediated hk2 upregulation also appears to operate in other types of cancer cells examined. We suggest that the miR-155/miR-143/HK2 axis may represent a common mechanism linking inflammation to the altered metabolism in cancer cells.
癌细胞优先通过有氧糖酵解来代谢葡萄糖。这种现象被称为瓦博格效应，是癌细胞葡萄糖代谢的异常特征。慢性炎症是肿瘤发生的一个关键促进因素。然而，促肿瘤炎症如何调节癌细胞中的葡萄糖代谢，在很大程度上仍未得到探索。在这里，我们表明促炎细胞因子促进乳腺癌细胞中的糖酵解，并且炎症诱导的 miR-155 在这个过程中作为一个重要的介质。我们进一步表明，miR-155 通过两种不同的机制来上调己糖激酶 2（hk2）。首先，miR-155 通过激活信号转导和转录激活因子 3（STAT3）来促进 hk2 的转录，STAT3 是 hk2 的转录激活因子。其次，通过靶向 C/EBPβ（mir-143 的转录激活因子），miR-155 抑制 mir-143，这是 hk2 的负调节剂，从而导致 hk2 的表达在转录后水平上调。miR-155 介导的 hk2 上调似乎也在其他类型的癌细胞中起作用。我们认为，miR-155/miR-143/HK2 轴可能代表将炎症与癌细胞代谢改变联系起来的一种共同机制。
