MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway
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Chuan He Yang1,2, Yinan Wang1,2, Michelle Sims1,2, Chun Cai2,3, Ping He2,4, Hans Häcker5, Junming Yue1,2, Jinjun Cheng1, Frederick A. Boop3 and Lawrence M. Pfeffer1,2,3
1Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
2Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
3Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
4Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
5Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Lawrence M. Pfeffer, email: [email protected]
Keywords: glioblastoma; ATM; miR-203; interferon; interferon signaling
Received: October 20, 2017 Accepted: November 26, 2017 Published: December 06, 2017
Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.
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