School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China.
Basic Res Cardiol. 2013 May;108(3):352. doi: 10.1007/s00395-013-0352-2. Epub 2013 May 1.
Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3'UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3'UTR activity. However, the over expression of DKK1 3'UTR or PTEN 3'UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.
竞争性内源 RNA（ceRNA）通过共享 miRNA 的隔离来调节含有共同 microRNA（miRNA）识别元件（MRE）的 mRNA 转录物。ceRNA 的相互作用已在癌细胞中得到证实。然而，相对于糖尿病和心肌中 ceRNA 相互作用的信息，目前还很少。本研究旨在评估 DKK1 和 PTEN 在利用其在糖尿病心肌细胞中的共同 miRNA 进行 ceRNA 调控中的潜在作用。在两种体内糖尿病模型（链脲佐菌素诱导的 1 型糖尿病小鼠和 db/db 小鼠）和体外（暴露于高血糖的人心肌细胞）中确定了 PTEN 和 DKK1 之间相互作用的调节。在所有三种糖尿病模型中，DKK1 和 PTEN（mRNA 和蛋白）的水平均平行上调。DKK1 以 miRNA 和 3'UTR 依赖性方式调节 PTEN 蛋白水平。RNAi 介导的 DKK1 基因沉默导致 PTEN 表达减少，反之亦然。当 Dicer 被抑制时，该作用被阻断。沉默 PTEN 或 DKK1 均可增加共享 miRNA 的可用性。沉默 PTEN 或 DKK1 均可抑制荧光素酶-PTEN 3'UTR 活性。然而，DKK1 3'UTR 或 PTEN 3'UTR 的过表达会增加其活性。DKK1 的衰减增加了 AKT 磷酸化，改善了高血糖暴露的 HCM 中的葡萄糖摄取并减少了细胞凋亡。这些作用被 PI3K 抑制所阻断。DKK1 和 PTEN 转录物在 DM 和高血糖中共同上调。DKK1 和 PTEN 作为 ceRNA，通过竞争结合 miRNA 来影响彼此的表达。
