EGF suppresses the expression of miR-124a in pancreatic β cell lines via ETS2 activation through the MEK and PI3K signaling pathways

Abstract

Diabetes mellitus is characterized by pancreatic β cell dysfunction. Previous studies have indicated that epidermal growth factor (EGF) and microRNA-124a (miR-124a) play opposite roles in insulin biosynthesis and secretion by beta cells. However, the underlying mechanisms remain poorly understood. In the present study, we demonstrated that EGF could inhibit miR-124a expression in beta cell lines through downstream signaling pathways, including mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) cascades. Further, the transcription factor ETS2, a member of the ETS (E26 transformation-specific) family, was identified to be responsible for the EGF-mediated suppression of miR-124a expression, which was dependent on ETS2 phosphorylation at threonine 72. Activation of ETS2 decreased miR-124a promoter transcriptional activity through the putative conserved binding sites AGGAANA/TN in three miR-124a promoters located in different chromosomes. Of note, ETS2 played a positive role in regulating beta cell function-related genes, including miR-124a targets, Forkhead box a2 (FOXA2) and Neurogenic differentiation 1 (NEUROD1), which may have partly been through the inhibition of miR-124 expression. Knockdown and overexpression of ETS2 led to the prevention and promotion of insulin biosynthesis respectively, while barely affecting the secretion ability. These results suggest that EGF may induce the activation of ETS2 to inhibit miR-124a expression to maintain proper beta cell functions and that ETS2, as a novel regulator of insulin production, is a potential therapeutic target for diabetes mellitus treatment.

ETS2 alleviates acute‐on‐chronic liver failure by suppressing excessive inflammation

“…ETS2 is a member of the Ets family of transcription factors that share a common conserved functional domain. ETS2 is expressed in a variety of cell types (endothelial cells, macrophages, and stromal fibroblasts) and has been implicated in various diseases, such as atherosclerosis, diabetes mellitus, and the cecal ligation and puncture‐induced sepsis 9,10,19–21 . This study demonstrates that ETS2 predicts the prognosis of ACLF and serves as a potential therapeutic target for ACLF.…”

“…***p < 0.001, ****p < 0.0001. GSEA, gene set enrichment analysis; LPS, lipopolysaccharide.puncture-induced sepsis 9,10,[19][20][21]. This study demonstrates that ETS2 predicts the prognosis of ACLF and serves as a potential therapeutic target for ACLF.…”

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

“…The neoepitope modification is thought to enhance binding affinity to high-risk HLA alleles compared to unmodified epitopes, which increases antigen presentation and recognition by T cells ( 111 , 112 ). An alternative explanation for the cause of epitope modification is that the defective insulin protein is expressed under stress: an unwanted response that can be inhibited by verapamil, a drug that reduces oxidative stress and insulin-processing defects ( 113 ). Nevertheless, the formation of neoantigens complexifies the development of immunotherapy, as these antigens are highly variable between subjects.…”

miRNAs provide mechanisms for integrated control of endocrine pancreas homeostasis and metabolic disease pathogenesis: a narrative review

“…miR-19b, miR-101a, miR-30b and miR-124a are other miRNA known to negatively regulate the insulin gene transcription by directly interacting with the transcription factor NeuroD1 (13,14,39). Interestingly for miR-124, the transcription factor Ets2 has been shown to mediate the effects of epidermal growth factor (EGF) inhibiting miR-124a expression (15).…”