College of Life Science, Northeast Forestry University, Harbin, China.
Int J Biol Sci. 2019 Sep 7;15(12):2561-2575. doi: 10.7150/ijbs.34985. eCollection 2019.
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.
糖尿病的特征是胰岛β细胞功能障碍。先前的研究表明，表皮生长因子（EGF）和 microRNA-124a（miR-124a）在β细胞胰岛素生物合成和分泌中发挥相反的作用。然而，其潜在机制仍知之甚少。在本研究中，我们通过下游信号通路（包括丝裂原活化蛋白激酶激酶（MEK）和磷脂酰肌醇 3-激酶（PI3K）级联）证实 EGF 可以抑制β细胞系中的 miR-124a 表达。此外，转录因子 ETS2，ETS（E26 转化特异性）家族的一员，被鉴定为负责 EGF 介导的 miR-124a 表达抑制的因子，该抑制依赖于 ETS2 在苏氨酸 72 位的磷酸化。ETS2 的激活通过位于不同染色体上的三个 miR-124a 启动子中的推定保守结合位点 AGGAANA/TN 降低 miR-124a 启动子转录活性。值得注意的是，ETS2 在调节β细胞功能相关基因中发挥了积极作用，包括 miR-124a 的靶基因 Forkhead box a2（FOXA2）和 Neurogenic differentiation 1（NEUROD1），这可能部分是通过抑制 miR-124 的表达。ETS2 的敲低和过表达分别导致胰岛素生物合成的预防和促进，而几乎不影响分泌能力。这些结果表明，EGF 可能诱导 ETS2 的激活以抑制 miR-124a 的表达，以维持适当的β细胞功能，并且 ETS2 作为胰岛素产生的新型调节剂，可能是治疗糖尿病的潜在治疗靶点。
