A novel transthyretin/STAT4/miR-223-3p/FBXW7 signaling pathway affects neovascularization in diabetic retinopathy
A novel transthyretin/STAT4/miR-223-3p/FBXW7 signaling pathway affects neovascularization in diabetic retinopathy
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DOI：
10.1016/j.mce.2019.110541
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发表时间：
2019-12-01
影响因子：
4.1
通讯作者：
Yao, Yong
中科院分区：
文献类型：
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作者：
Shao, Jun;Fan, Guangming;Yao, Yong
MicroRNAs（miRNAs）是一类不具有蛋白质编码功能的小分子RNA，负调控靶基因，在生理和病理过程中发挥重要作用。本研究的目的是揭示糖尿病视网膜病变（DR）中一种新的miRNA/基因通路。使用微阵列筛选来自非糖尿病对照和DR患者的样本中的miRNA，并筛选miR-223- 3 p作为潜在候选者。实时荧光定量PCR（qRT-PCR）结果显示，高血糖状态下DR标本和人视网膜内皮细胞（hRECs）中miR-223- 3 p的表达频繁增加，但在高血糖状态下加入甲状腺素运载蛋白（TTR）后，miR-223- 3 p的表达水平降低。此外，根据细胞增殖、管形成和伤口愈合测定，miR-223- 3 p的下调抑制细胞迁移和增殖，而miR-223- 3 p的上调显示出相反的效果。此外，荧光素酶测定将F-box和WD重复结构域7（FBXW 7）鉴定为miR-223- 3 p的靶mRNA。高糖条件促进信号转导和转录激活因子4（STAT 4）的募集，促进miR-2233 p的转录。在hRECs中，在高血糖环境中，TTR抑制STAT 4表达，下调miR-223- 3 p水平，最终促进FBXW 7表达。这项研究发现了一种新的机制，TTR可能通过新发现的DR中的STAT 4/miR-223- 3 p/FBXW 7级联影响新生血管形成。
MicroRNAs (miRNAs) are small RNAs without protein-coding functions that negatively regulate target genes and play important roles in physiological and pathological processes. The aim of this work was to reveal a novel miRNA/gene pathway in diabetic retinopathy (DR). A microarray was used to screen miRNAs in samples from nondiabetic controls and patients with DR, and miR-223-3p was screened as a potential candidate. Quantitative real-time PCR (qRT-PCR) revealed that the level of miR-223-3p was frequently overexpressed in DR samples and human retinal endothelial cells (hRECs) in hyperglycemia, but it was decreased in hyperglycemia after the addition of transthyretin (TTR). In addition, according to cell proliferation, tube formation, and wound healing assays, the downregulation of miR-223-3p suppressed cell migration and proliferation, whereas miR-223-3p upregulation showed the opposite effects. Furthermore, luciferase assays identified F-box and WD repeat domain-containing 7 (FBXW7) as a target mRNA of miR-223-3p. High glucose conditions facilitated the recruitment of signal transducer and activator of transcription 4 (STAT4) and promoted the transcription of miR-2233p. In hRECs, in a hyperglycemic environment, TTR inhibited STAT4 expression, downregulated the level of miR-223-3p, and finally promoted FBXW7 expression. This study found a novel mechanism whereby TTR might affect neovascularization through a newly identified STAT4/miR-223-3p/FBXW7 cascade in DR.