Abstract
miR-21 is an oncogenic microRNA (miRNA) that is upregulated in many solid tumors. However, the effect of MIR21 hypomethylation on miR-21 expression in tumors and the mechanism of miR-21 DNA demethylation remain unclear. In this study, we confirmed that the expression of miR-21 was significantly increased in multiple tumors. We analyzed eight types of cancer, including breast cancer (BRCA), lung adenocarcinoma (LUAD), renal and renal clear cell carcinoma (KIRC), bladder urothelial carcinoma (BLCA), hepatocellular carcinoma (LIHC), lung squamous cell cancer (LUSC), renal papillary cell carcinoma (KIRP), and pancreatic adenocarcinoma (PAAD). MIR21 DNA methylation levels were elevated in these cancers. CpG loci located approximately 200 bp upstream of the transcription initiation site strongly affect MIR21 expression. We also confirmed MIR21 hypomethylation by pyrosequencing of fresh clear cell renal cell carcinoma (ccRCC) samples. Demethylating agent was proved to increase hsa-miR-21-5p level in HEK293T cells, while knockdown of DNA demethylases TET3 and TDG decreased MIR21 expression. In addition, we showed that the cg02515217 CpG locus in MIR21 promoter was a conserved binding site of transcription factors CEBPB, MEIS3, and TEAD4, which were co-expressed with miR-21 in tumors. These observations identified that gene hypomethylation regulated the expression of MIR21 in tumors.
Highlights
MicroRNAs are non-coding RNAs of approximately 21– 25 bases in length. miRNAs exert a negative regulatory effect through complementary binding of the 30 untranslated regions (30 UTRs) of the target gene, either causing target gene mRNA degradation or translational inhibition. miRNA is closely related to cell proliferation, differentiation, and apoptosis, especially the occurrence and development of tumors.121 in breast cancer cells by fluorescence reporter gene analysis and western blot.[5]
MIR21 Expression in The Cancer Genome Atlas (TCGA) Data To demonstrate the expression of MIR21 in tumors and its relationship with tumor prognosis, we downloaded the expression analysis miR-21 is an oncogenic miRNA that is upregulated in many solid tumors and non-solid tumors.[2]
Among six cancer types, including kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), LIHC, lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD), low hsa-miR-21-5p was significantly associated with better survival compared with patients with high hsa-miR-21-5p expression (Figure 1C; hazard ratio [HR] > 1, p < 0.05)
Summary
MicroRNAs (miRNAs) are non-coding RNAs of approximately 21– 25 bases in length. miRNAs exert a negative regulatory effect through complementary binding of the 30 untranslated regions (30 UTRs) of the target gene, either causing target gene mRNA degradation or translational inhibition. miRNA is closely related to cell proliferation, differentiation, and apoptosis, especially the occurrence and development of tumors.121 in breast cancer cells by fluorescence reporter gene analysis and western blot.[5]. MiRNA expression is regulated by both transcription factors and epigenetics.[7] DNA methylation is an important way of epigenetic modification, affecting gene expression and cell development without changing the DNA sequence. DNA methylation can occur within the gene bodies, transcription initiation sites with or without the CpG island, and at regulatory elements and repeat sequences.[8] In many tumor tissues, the specific tumor suppressor gene is hypermethylated, leading to abnormally low expression, or the oncogene is hypomethylated, leading to abnormally high expression.[9] The Cancer Genome Atlas (TCGA) research reported that overexpression of miR-21 is associated with hypomethylation of the MIR21 promoter in clear cell renal cell carcinoma (ccRCC)[10] and papillary thyroid carcinoma (PTC).[11] there are currently few reports on MIR21 methylation and CpG locus that affect MIR21 expression in other tumors
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