標題: Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma
作者: Chiou, Guang-Yuh
Chien, Chian-Shiu
Wang, Mong-Lien
Chen, Ming-Teh
Yang, Yi-Ping
Yu, Yung-Luen
Chien, Yueh
Chang, Yun-Ching
Shen, Chiung-Chyi
Chio, Chung-Ching
Lu, Kai-Hsi
Ma, Hsin-I
Chen, Kuan-Hsuan
Liu, Dean-Mo
Miller, Stephanie A.
Chen, Yi-Wei
Huang, Pin-I
Shih, Yang-Hsin
Hung, Mien-Chie
Chiou, Shih-Hwa
材料科學與工程學系
Department of Materials Science and Engineering
公開日期: 12-Dec-2013
摘要: 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.
URI: http://dx.doi.org/10.1016/j.molcel.2013.11.009
http://hdl.handle.net/11536/23416
ISSN: 1097-2765
DOI: 10.1016/j.molcel.2013.11.009
期刊: MOLECULAR CELL
Volume: 52
Issue: 5
起始頁: 693
結束頁: 706
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