Tumor-Suppressive miR148a Is Silenced by CpG Island Hypermethylation in IDH1-Mutant Gliomas

Abstract

Purpose IDH1/2 mutant gliomas harbor a distinct CpG island methylation profile (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor suppressive genes. The potential role of tumor suppressive miRNAs in this process is not understood. Experimental Design To identify potential tumor suppressive microRNAs 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 TaqMan qPCR. Functional analyses of miRNA-148a were conducted and target genes were identified. Results We identify miR-148a as a novel, G-CIMP associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in malignant glioma patients. We confirm that down-regulation of miR-148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR-148a methylation and downregulation, and that restoration of miR-148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1. Conclusions We identify miR-148a as a novel G-CIMP associated miRNA, and provide results suggesting that miR-148a restoration may have therapeutic implications.

MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations

“…MiR-148a was reported to be downregulated in IDH1 R132H gliomas due to miR148a promoter hypermethylation [35]. This contradicts our finding that miR-148a is upregulated in IDH1 R132H glioma tissues.…”

MiR-148a, a microRNA upregulated in the WNT subgroup tumors, inhibits invasion and tumorigenic potential of medulloblastoma cells by targeting Neuropilin 1

“…MiR-148a expression has been reported to reduce growth, tumorigenic potential and invasion potential of various cancer cells including HBx expressing hepatocarcinoma cells, gastric cancer cells, pancreatic cancer cell lines and prostate cancer cell lines [11-14]. Recently miR-148a has also been reported to inhibit glioma stem cell-like properties and tumorigenicity [15, 16]. Thus, tumor suppressive effect of miR-148a expression in medulloblastoma cells is consistent with its role in other cancers.…”

Emerging technologies for studying DNA methylation for the molecular diagnosis of cancer

“…Recently, this protocol was optimized to analyze nanograms of genomic DNA. RRBS has been used to generate genome-wide DNA methylation maps of gliomas [192], leukemia [193], and colon cancer [194]. …”