MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway

Chuan Yang, Yinan Wang, Michelle Sims, Chun Cai, Ping He, Hans Häcker, Junming Yue, Jinjun Cheng, Frederick Boop, Lawrence Pfeffer

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)112980-112991
Number of pages12
JournalOncotarget
Volume8
Issue number68
DOIs
StatePublished - Jan 1 2017

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Ataxia Telangiectasia
Glioblastoma
Glioma
Interferons
Carcinogenesis
temozolomide
Cell Line
Cell Movement
Ataxia Telangiectasia Mutated Proteins
Cell Proliferation
Apoptosis
MicroRNAs
Brain Neoplasms
Tyrosine
Neoplasms
Phosphotransferases
Phosphorylation
Phenotype
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway. / Yang, Chuan; Wang, Yinan; Sims, Michelle; Cai, Chun; He, Ping; Häcker, Hans; Yue, Junming; Cheng, Jinjun; Boop, Frederick; Pfeffer, Lawrence.

In: Oncotarget, Vol. 8, No. 68, 01.01.2017, p. 112980-112991.

Research output: Contribution to journalArticle

Yang, Chuan ; Wang, Yinan ; Sims, Michelle ; Cai, Chun ; He, Ping ; Häcker, Hans ; Yue, Junming ; Cheng, Jinjun ; Boop, Frederick ; Pfeffer, Lawrence. / MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway. In: Oncotarget. 2017 ; Vol. 8, No. 68. pp. 112980-112991.
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