Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

Guang-Yuh Chiou; Chian-Shiu Chien; Mong-Lien Wang; Ming-Teh Chen; Yi-Ping Yang; Yung-Luen Yu; Yueh Chien; Yun-Ching Chang; Chiung-Chyi Shen; Chung-Ching Chio; Kai-Hsi Lu; Hsin-I Ma; Kuan-Hsuan Chen; Dean-Mo Liu; Stephanie A Miller; Yi-Wei Chen; Pin-I Huang; Yang-Hsin Shih; Mien-Chie Hung; Shih-Hwa Chiou

doi:10.1016/j.molcel.2013.11.009

Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

Mol Cell. 2013 Dec 12;52(5):693-706. doi: 10.1016/j.molcel.2013.11.009.

Authors

Guang-Yuh Chiou¹, Chian-Shiu Chien², Mong-Lien Wang³, Ming-Teh Chen⁴, Yi-Ping Yang³, Yung-Luen Yu⁵, Yueh Chien⁶, Yun-Ching Chang⁶, Chiung-Chyi Shen⁷, Chung-Ching Chio⁸, Kai-Hsi Lu⁹, Hsin-I Ma¹⁰, Kuan-Hsuan Chen¹¹, Dean-Mo Liu¹², Stephanie A Miller¹³, Yi-Wei Chen¹⁴, Pin-I Huang¹⁴, Yang-Hsin Shih⁴, Mien-Chie Hung¹⁵, Shih-Hwa Chiou¹⁶

Affiliations

¹ Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
² Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan.
³ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Cancer Research Center, National Yang-Ming University, Taipei 112, Taiwan.
⁴ School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
⁵ Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
⁶ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
⁷ School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taichung Veterans General Hospital, Taichung 407, Taiwan.
⁸ Department of Neurosurgery, Chi-Mei Medical Center, Tainan 710, Taiwan.
⁹ Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei 112, Taiwan.
¹⁰ Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan.
¹¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
¹² Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu 300, Taiwan.
¹³ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
¹⁴ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
¹⁵ Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. Electronic address: mhung@mdanderson.org.
¹⁶ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Cancer Research Center, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan. Electronic address: shchiou@vghtpe.gov.tw.

PMID: 24332177
DOI: 10.1016/j.molcel.2013.11.009

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Base Sequence
Brain Neoplasms / genetics*
Cell Line, Tumor
DNA Methylation
Epigenesis, Genetic
Female
Glioblastoma / genetics*
HMGA2 Protein / genetics
Humans
Interleukin-6 / genetics*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
Middle Aged
Molecular Sequence Data
Promoter Regions, Genetic
SOXB1 Transcription Factors / genetics
Up-Regulation

Substances

3' Untranslated Regions
HMGA2 Protein
Interleukin-6
MIRN142 microRNA, human
MicroRNAs
SOX2 protein, human
SOXB1 Transcription Factors