DNA Methylation Influences miRNA Expression in Gonadotroph Pituitary Tumors

Abstract

microRNAs are involved in pathogenesis of cancer. DNA methylation plays a role in transcription of miRNA-encoding genes and may contribute to changed miRNA expression in tumors. This issue was not investigated in pituitary neuroendocrine tumors (PitNETs) previously. DNA methylation patterns, assessed with HumanMethylation450K arrays in 34 PitNETs and five normal pituitaries, were used to determine differentially methylated CpGs located at miRNA genes. It showed aberrant methylation in regions encoding for 131 miRNAs. DNA methylation data and matched miRNA expression profiles, determined with next-generation sequencing (NGS) of small RNAs, were correlated in 15 PitNETs. This showed relationship between methylation and expression levels for 12 miRNAs. DNA methylation and expression levels of three of them (MIR145, MIR21, and MIR184) were determined in the independent group of 80 tumors with pyrosequencing and qRT-PCR and results confirmed both aberrant methylation in PitNETs and correlation between methylation and expression. Additionally, in silico target prediction was combined with analysis of established miRNA profiles and matched mRNA expression pattern, assessed with amplicon-based NGS to indicate putative target genes of epigenetically deregulated miRNAs. This study reveals aberrant DNA methylation in miRNA-encoding genes in gonadotroph PitNETs. Methylation changes affect expression level of miRNAs that regulate putative target genes with tumorigenesis-relevant functions.

Glaucocalyxin A Inhibits the Malignancies of Gastric Cancer Cells by Downregulating MDM2 and RNF6 via MiR-3658 and the SMG1-UPF mRNA Decay Pathway

“…In addition to the miR-3658 pathway, our pathway analysis data in GC cells treated with GLA showed that GLA could activate the SMG1-UPF pathway that functions to downregulate the expression of various essential factors facilitating tumorigenesis by inducing mRNA decay ( 26 , 27 ). The SMG1-UPF pathway is a core part of NMD, a quality-control mechanism that rapidly degrades aberrant mRNAs ( 22 , 23 ). Impairment of NMD-mediated mRNA degradation against oncogenesis is involved in various pathophysiological processes of cancer ( 44 – 46 ).…”

“…Since miR-3658 could act as a tumor suppressor microRNA and is downregulated in gastric cancer, we sought to explore the mechanism underlying the restoration of miR-3658 by GLA in GC cells. Cancer-related aberrant methylation is commonly observed in miRNA genes, and the hypermethylation leads to the downregulation of the expression of tumor-suppressive miRNAs in cancer cells (22)(23)(24)(25). To investigate whether DNA methylation is involved in the downregulation of miR-3658 in GC cells, we treated GC cells with 5-Aza-CdR, an S-phasespecific demethylating agent, to induce demethylation.…”

Inflammatory microRNAs in cardiovascular pathology: another brick in the wall

“…Methylation is another process that may alter miRNA expression. Genes transcribing inflamma-miRs such as miR-21 and mir-145 have been shown to be hypermethylated in gonadotroph pituitary tumors ( 132 ). A recent review by Pajares et al.…”

miR-22 Suppresses EMT by Mediating Metabolic Reprogramming in Colorectal Cancer through Targeting MYC-Associated Factor X

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