Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2010 Aug 27;39(4):493-506. doi: 10.1016/j.molcel.2010.07.023.
A transient inflammatory signal can initiate an epigenetic switch from nontransformed to cancer cells via a positive feedback loop involving NF-kappaB, Lin28, let-7, and IL-6. We identify differentially regulated microRNAs important for this switch and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL-6, directly activates miR-21 and miR-181b-1. Remarkably, transient expression of either microRNA induces the epigenetic switch. MiR-21 and miR-181b-1, respectively, inhibit PTEN and CYLD tumor suppressors, leading to increased NF-kappaB activity required to maintain the transformed state. These STAT3-mediated regulatory circuits are required for the transformed state in diverse cell lines and tumor growth in xenografts, and their transcriptional signatures are observed in colon adenocarcinomas. Thus, STAT3 is not only a downstream target of IL-6 but, with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer.
短暂的炎症信号可以通过涉及 NF-κB、Lin28、let-7 和 IL-6 的正反馈回路，将非转化细胞转变为癌细胞的表观遗传开关。我们确定了对这种开关重要的差异调节的 microRNAs 及其启动子中假定的转录因子结合位点。STAT3 是一种被 IL-6 激活的转录因子，可直接激活 miR-21 和 miR-181b-1。值得注意的是，微 RNA 的瞬时表达可诱导表观遗传开关。miR-21 和 miR-181b-1 分别抑制 PTEN 和 CYLD 肿瘤抑制因子，导致维持转化状态所需的 NF-κB 活性增加。这些 STAT3 介导的调节回路是不同细胞系转化状态和异种移植物中肿瘤生长所必需的，并且在结肠腺癌中观察到其转录特征。因此，STAT3 不仅是 IL-6 的下游靶标，而且与 miR-21、miR-181b-1、PTEN 和 CYLD 一起，是构成连接炎症与癌症的表观遗传开关的正反馈回路的一部分。
