1. Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma.
- Author
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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, and Chiou, Shih-Hwa
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GLIOBLASTOMA multiforme treatment , *EPIGENETICS , *MICRORNA , *INTERLEUKIN-6 , *CARCINOGENESIS , *CYTOKINES , *CANCER invasiveness - Abstract
Summary: 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 stemness. 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 feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target. [Copyright &y& Elsevier]
- Published
- 2013
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