MiR-134, epigenetically silenced in gliomas, could mitigate the malignant phenotype by targeting KRAS

By integrating miRNA expression data of three glioma cell lines before and after 5-AZA treatment, we find miR-134 is silenced in glioma by promoter hypermethylation. The methylation and expression levels of miR-134 are validated in independent samples by bisulfite sequencing, qRT-PCR and expression...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2018-03, Vol.39 (3), p.389-396
Main Authors: Wang, Zhi-liang, Zhang, Chuan-bao, Wang, Zheng, Meng, Xiang-qi, Liu, Xiao-juan, Han, Bo, Duan, Chun-bin, Cai, Jin-quan, Hao, Zhong-fei, Chen, Ming-hui, Jiang, Tao, Li, Yong-li, Jiang, Chuan-lu, Wang, Hong-jun
Format: Article
Language:English
Subjects:
Animals
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Gene Expression Regulation, Neoplastic - genetics
Gene Silencing
Glioma - genetics
Glioma - pathology
Heterografts
Humans
Mice
Mice, Inbred BALB C
MicroRNAs - genetics
Phenotype
Proto-Oncogene Proteins p21(ras) - genetics
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Summary:By integrating miRNA expression data of three glioma cell lines before and after 5-AZA treatment, we find miR-134 is silenced in glioma by promoter hypermethylation. The methylation and expression levels of miR-134 are validated in independent samples by bisulfite sequencing, qRT-PCR and expression microarray. KRAS, the key target of miR-134, is upregulated and promote the malignant phenotype of glioma in consequence. Abstract Gliomas are characterized by a malignant phenotype with proliferation, cell cycle arrest and invasion. To explore the biological consequences of epigenetically regulated miRNAs, we performed a microarray-based screening (whose expression was affected by 5-AZA treatment) followed by bisulfite sequencing validation. We found that miR-134 as an epigenetically regulated suppressor gene with prognostic value in gliomas. MicroRNA-134 was downregulated in high-grade gliomas, especially in GBM samples. Functional studies in vitro and in vivo in mouse models showed that overexpression of miR-134 was sufficient to reduce cell cycle arrest, cell proliferation and invasion. Target analysis and functional assays correlated the malignant phenotype with miR-134 target gene KRAS, an established upstream regulator of ERK and AKT pathways. Overall, our results highlighted a role for miR-134 in explaining the malignant phenotype of gliomas and suggested its relevance as a target to develop for early diagnostics and therapy.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgy022