Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma
Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma
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DOI：
10.1016/j.molcel.2013.11.009
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发表时间：
2013-12-12
期刊：
影响因子：
16
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
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作者：
Chiou, Guang-Yuh;Chien, Chian-Shiu;Chiou, Shih-Hwa
表观遗传调控在胶质母细胞瘤（GBM）肿瘤发生中起着关键作用。然而，microRNAs （miRNAs）和细胞因子如何协同调节GBM肿瘤进展尚不清楚。在这里，我们发现白细胞介素-6 （IL-6）通过诱导DNA甲基转移酶1介导的miR142-3p启动子的高甲基化，抑制miR142-3p的表达，促进GBM的繁殖。有趣的是，miR142-3p也通过靶向IL-6的3' UTR抑制IL-6的分泌。此外，miR142-3p还靶向3' UTR，抑制高迁移率基团AT-hook 2 （HMGA2）的表达，从而抑制sox2相关的严重度。我们进一步发现HMGA2通过直接结合Sox2启动子来增强Sox2的表达。在临床上，肿瘤出现IL-6、HMGA2和Sox2蛋白表达上调以及miR142-3p启动子高甲基化的GBM患者也表现出较差的生存结果。原位传递miR142-3p可阻断IL-6/HMGA2/Sox2的表达并抑制gbm异种移植小鼠的茎样特性。总之，我们发现了一种IL-6/miR142-3p反馈环依赖性的GBM恶性肿瘤调节，可能是一个潜在的治疗靶点。
Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related sternness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feed-back-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.