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MiR-25 and miR-92a regulate insulin I biosynthesis in rats.

ABSTRACT: The 3' UTR of insulin has been identified as a critical region that confers mRNA stability, which is crucial for promoting transcription in response to glucose challenge. miRNAs are endogenously encoded non-coding RNAs that function as regulators of gene expression. This regulatory function is generally mediated by complementary binding to the 3'UTR of its mRNA targets that affects subsequent translational process. Genes involved in the regulation of glucose homeostasis, particularly in insulin production, have been found as targets of several miRNAs. Yet, no direct miRNA-based regulators of insulin biosynthesis have been identified. In this study, identification of possible miRNA-based regulators of insulin production is explored. Members of a miRNA family, miR-25 and miR-92a, are found as direct modulators of insulin expression. Overexpression of miR-25 or miR-92a reduced insulin expression while inhibition of miR-25 and miR-92a expression using corresponding antagomiRs promoted insulin expression and ultimately enhanced glucose-induced insulin secretion. Furthermore, suppression of insulin secretion by pre miR-9 could be attenuated by treatment with anti-miR-25 or miR-92a. Interestingly, we found the binding site of miR-25 and miR-92a to overlap with that of PTBP1, an important RNA binding molecule that stabilizes insulin mRNA for translation. Despite the increase in PTBP1 protein in the pancreas of diabetic rats, we observed insulin expression to be reduced alongside upregulation of miR-25 and miR-92a, suggesting an intricate regulation of insulin (bio)synthesis at its mRNA level.

SUBMITTER: Setyowati Karolina D

PROVIDER: S-EPMC3817158 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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miR-25 and miR-92a regulate insulin I biosynthesis in rats.

Setyowati Karolina Dwi D Sepramaniam Sugunavathi S Tan Hui Zhing HZ Armugam Arunmozhiarasi A Jeyaseelan Kandiah K

RNA biology 20130801 8

The 3' UTR of insulin has been identified as a critical region that confers mRNA stability, which is crucial for promoting transcription in response to glucose challenge. miRNAs are endogenously encoded non-coding RNAs that function as regulators of gene expression. This regulatory function is generally mediated by complementary binding to the 3'UTR of its mRNA targets that affects subsequent translational process. Genes involved in the regulation of glucose homeostasis, particularly in insulin ...[more]

PMID: 24084692

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Project description:BACKGROUND: Plasma microRNA (miRNA) has become a promising biomarker for detecting cancer; however, it remains uncertain whether miRNA expression levels in plasma reflect those in tumor cells. Our aim was to determine the biological relevance of miR-92a, which has been implicated as an oncomiR in both plasma and leukemia cells in patients with acute leukemia and to evaluate whether it could be a novel biomarker for monitoring these patients. RESULTS: We quantified the expression level of miR-92a in both cells and plasma by reverse transcription polymerase chain reaction in 91 patients with acute leukemia. We also determined miR-92a expression levels in peripheral blood mononuclear cells (PBMNC) from normal controls. We compared miR-92a expression in plasma with its expression in leukemia cells. Synthetic anti-miR-92a inhibitor was transfected into Raji and OM9;22 cells, and apoptosis was assessed. For in vivo assessment, 6-week-old female nude mice were injected with U937 cells, and miR-92a expression in plasma and tumors was measured. The level of miR-92a expression in fresh leukemia cells was highly variable compared with PBMNC, but significantly lower compared with CD34-positive cells obtained from healthy volunteers. We also noticed that miR-92a was preferentially expressed in acute lymphoblastic leukemia (ALL) cells in comparison with acute myeloid leukemia (AML) cells. More specifically, cellular miR-92a expression was significantly increased in a subset of ALL cells, and ALL patients with overexpressed miR-92a had poor prognoses. The anti-miR-92a inhibitor-treated Raji and OM9;22 cells revealed an increase of apoptotic cells. Notably, the cell to plasma ratio of miR-92a expression was significantly higher in both AML and ALL cells compared with PBMNC from healthy volunteers. In tumor-bearing mice, the plasma miR-92a level was significantly decreased in accordance with tumor growth, while tumor tissue was strongly positive for miR-92a. CONCLUSIONS: The miR-92a expression in leukemia cells could be a prognostic factor in ALL patients. The inverse correlation of miR-92a expression between cells and plasma and the cell to plasma ratio may be important to understanding the clinical and biological relevance of miR-92a in acute leukemia.

Project description:BackgroundMiR-92a-3p and oxidative stress are associated with catheter-related thrombosis (CRT). As a kind of physical intervention, resistance exercise can effectively promote blood circulation. In this study, we investigated the roles of miR-92a-3p, oxidative stress and the P38 mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) pathway in CRT during resistance exercise.MethodsThe rat CRT model was used for resistance exercise intervention. Moreover, pathological changes from the right jugular vein to the right auricle were observed under an electron microscope. In addition, reactive oxygen species (ROS) production, malondialdehyde (MDA) activity and heme oxygenase (HO-1) level in rat serum were detected via ELISA. The expression levels of miR-92A-3p and HO-1 in the vascular tissues of the rats were determined via real-time quantitative PCR. Additionally, the expression levels of HO-1, NF-κB P65, p38MAPK and IκBa in the venous tissues of the rats were analysed by Western blot analysis.ResultsThe pathological results showed that the thrombosis incidence rate in the CRT + RE group was lower than that in the CRT group. In the CRT group, the expression levels of ROS and MDA, which are markers related to oxidative stress in serum, significantly increased whilst the expression of HO-1 decreased. In the venous tissue, the expression of miR-92a-3p increased, the level of HO-1 decreased, the levels of p38MAPK and NF-κB p65 significantly increased but that of P-IκBa and IκBa significantly decreased. In the CRT + RE group, after administering the resistance exercise intervention, ROS production and MDA activity in serum significantly decreased, the expression level of HO-1 increased and the expression level of miR-92a-3p in the venous tissues significantly decreased and was negatively correlated with that of HO-1. The levels of p38MAPK and NF-κB p65 significantly decreased but that of P- IκBa and IκBa significantly increased.ConclusionResistance exercise intervention downregulated miR-92a-3p expression, repaired oxidative stress injury and prevented CRT formation.

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MiR-25 and miR-92a regulate insulin I biosynthesis in rats.

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miR-25 and miR-92a regulate insulin I biosynthesis in rats.

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