Dataset Information

Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer.

ABSTRACT: Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumorigenesis and development. Although the low expression of miR-125a-5p in gastric cancer has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in gastric cancer was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the GC islands in the miR-125a-5p region were hypermethylated in the tumour tissues. And the hypermethylation was negatively correlated with the miR-125a-5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR-125a-5p could directly suppress the Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, the Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a-5p could also self-activate the silenced miR-125a-5p in gastric cancer cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo. Thus, we uncovered here that the epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer, suggesting that miR-125a-5p might be not only the potential prognostic value as a tumour biomarker but also potential therapeutic targets in gastric cancer.

SUBMITTER: Cai M

PROVIDER: S-EPMC6156292 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer.

Cai Mingzhi M Chen Qiuxian Q Shen Juntao J Lv Chenbing C Cai Lisheng L

Journal of cellular and molecular medicine 20180817 10

Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumorigenesis and development. Although the low expression of miR-125a-5p in gastric cancer has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in gastric cancer was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the GC islands in the miR-125a-5p region were hypermethylated in the tumour tissues. And the hypermethylation w ...[more]

PMID: 30117667

Similar Datasets

Project description:BackgroundRecently, many microRNAs have been found to be involved in the cancer progression including miR-125a. However, the underlying mechanisms of miR-125a in gastric cancer (GC) remain to be completely elucidated.ObjectiveThe study was to investigate the functional role of miR-125a and the expression relevance of signal transducer and activator of transcription 3 (STAT3) and hyaluronan synthase 1 (HAS1).MethodCCK-8 assay, scratch wound healing and transwell assay were conducted to identify the functional role of miR-125a in GC. In addition, using bioinformatics analysis, the target regulation relationship was found in STAT3 and miR-125a. To confirm the relationship, luciferase reporter assay was performed. More importantly, quantitative polymerase chain reaction and western blot assay were carried out to determine the association among miR-125a, STAT3 and HAS1 in GC cells.ResultsOverexpressed miR-125a inhibited the migration and invasion of GC cells through scratch wound healing and transwell assay, and its knockdown displayed adverse effects, but the viability of GC cells did not show significant difference using CCK-8 assay. In addition, we identified that the knockdown of STAT3 or HAS1 remarkably suppressed the migration and invasion abilities of GC cells. Using bioinformatics analysis, miRTar, in particular, indicated that the 3'-untranslated region of STAT3 binds to miR-125a with a high score. Subsequently, we also verified that STAT3 was a target of miR-125a via luciferase reporter assay. Furthermore, we found that upregulated miR-125a expression could conspicuously constrain STAT3 expression at both protein and mRNA levels in MKN45 and NCI-N87 cells using quantitative polymerase chain reaction and Western blot assay, but no significant difference had been found in SGC 7901 cells. To further identify the regulatory relationship between miR-125a and STAT3, downregulation of miR-125a in MKN45 and NCI-N87 cells was carried out, which showed that the protein and mRNA expression levels of STAT3 were declined in two cell lines. Finally, we observed that upregulated miR-125a could lead to the decrease of HAS1 at protein and mRNA levels, whereas its knockdown revealed opposite effects. Meanwhile, we noticed that overexpression of STAT3 could induce the escalation of HAS1 at protein and mRNA expression levels and its knockdown exhibited the adverse outcomes.ConclusionThese findings indicated that miR-125a may control the HAS1 expression in GC progression by targeting STAT3, which is likely to facilitate a better understanding of the regulation mechanisms of miR-125a in GC.

Project description:Glycolipid metabolic disorder is an important cause for the development of type 2 diabetes mellitus (T2DM). Clarification of the molecular mechanism of metabolic disorder and exploration of drug targets are crucial for the treatment of T2DM. Methods: We examined miR-125a-5p levels in palmitic acid-induced AML12 cells and the livers of type 2 diabetic rats and mice, and then validated its target gene. Through gain- and loss-of-function studies, the effects of miR-125a-5p via targeting of STAT3 on regulating glycolipid metabolism were further illustrated in vitro and in vivo. Results: We found that miR-125a-5p was significantly decreased in the livers of diabetic mice and rats, and STAT3 was identified as the target gene of miR-125a-5p. Overexpression of miR-125a-5p in C57BL/6 mice decreased STAT3 level and downregulated the expression levels of p-STAT3 and SOCS3. Consequently, SREBP-1c-mediated lipogenesis pathway was inhibited, and PI3K/AKT pathway was activated. Moreover, silencing of miR-125a-5p significantly increased the expression levels of STAT3, p-STAT3 and SOCS3, thus activating SREBP-1c pathway and suppressing PI3K/AKT pathway. Therefore, hyperglycemia, hyperlipidemia and decreased liver glycogen appeared in C57BL/6 mice. In palmitic acid-induced AML12 cells, miR-125a-5p mimic markedly increased glucose consumption and uptake and decreased the accumulation of lipid droplets by regulating STAT3 signaling pathway. Consistently, miR-125a-5p overexpression obviously inhibited STAT3 expression in diabetic KK-Ay mice, thereby decreasing blood glucose and lipid levels, increasing hepatic glycogen content, and decreasing accumulation of hepatic lipid droplets in diabetic mice. Furthermore, inhibition of miR-125a-5p in KK-Ay mice aggravated glycolipid metabolism dysfunction through regulating STAT3. Conclusions: Our results confirmed that miR-125a-5p should be considered as a regulator of glycolipid metabolism in T2DM, which can inhibit hepatic lipogenesis and gluconeogenesis and elevate glycogen synthesis by targeting STAT3.

Dataset Information

Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer.

Publications

Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets