In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 22 ( 2014-11-15), p. 5808-5822
Abstract:
Purpose: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood. Experimental Design: To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2WT gliomas (n = 11) and IDH1MUT glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1WT and 72 IDH1/2MUT samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified. Results: We identify miR148a as a novel, G-CIMP–associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1. Conclusions: We identify miR148a as a novel G-CIMP–associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications. Clin Cancer Res; 20(22); 5808–22. ©2014 AACR.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-14-0234
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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