miR‐184 regulates ezrin, LAMP‐1 expression, affects phagocytosis in human retinal pigment epithelium and is downregulated in age‐related macular degeneration

Abstract

MicroRNA 184 (miR-184) is known to play a key role in neurological development and apoptosis and is highly expressed in mouse brain, mouse corneal epithelium, zebrafish lens and human retinal pigment epithelium (RPE). However, the role of miR-184 in RPE is largely unknown. We investigated the role of miR-184 in RPE and its possible implication in age-related macular degeneration (AMD). Proteomic analysis identified the ezrin (EZR) gene as a target of miR-184 in human RPE. EZR is a membrane cytoskeleton crosslinker that is also known to bind to lysosomal-associated membrane protein 1 (LAMP-1) during the formation of phagocytic vacuoles. In adult retinal pigment epithelium 19 (ARPE19) cells, inhibition of miR-184 resulted in upregulation of EZR mRNA and EZR protein, and induced downregulation of LAMP-1. The inhibition of miR-184 decreased EZR-bound LAMP-1 protein levels and affected phagocytic activity in ARPE19 cells. In primary culture of human RPE isolated from eyes of AMD donors (AMD RPE), miR-184 was significantly downregulated compared with control (normal) RPE. Downregulation of miR-184 was consistent with significantly lower levels of LAMP-1 protein in AMD RPE, and overexpression of MIR-184 in AMD RPE was able to rescue LAMP-1 protein expression to normal levels. Altogether, these observations suggest a novel role for miR-184 in RPE health and support a model proposing that downregulation of miR-184 expression during aging may result in dysregulation of RPE function, contributing to retinal degeneration.

MicroRNA-182 Suppresses HGF/SF-Induced Increases in Retinal Pigment Epithelial Cell Proliferation and Migration through Targeting c-Met

“…There have been only a few studies describing the roles of miRNAs in their posttranscriptional inhibition of gene expression in RPE cells. Specifically, these studies described: a) miR-204/211 involvement in maintaining the RPE phenotype [23]; b) miR-34a maintaining RPE cells quiescent and stationary [18]; c) differentially expressed miRNAs in TGFβ-induced EMT in RPE cells [24], and miR-124 involvement in this process [25]; e) the role of miR-23a [26] and miR-184 [27] in age-related macular degeneration. However, to the best of our knowledge we are not aware of any reports describing any involvement of a change in miRNA expression in clinical PVR tissue samples.…”

MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway

“…Mature miR-184, containing 22 nucleotides, shows tissue and developmental stage specific expression patterns [17, 18]. It is selectively enriched in mouse brain, mouse corneal epithelium, zebrafish lens and human RPE [19], and is involved in neurological development, apoptosis, and cell differentiation [20, 21]. Previous study has revealed that miR-184 expression is decreased in RPE of AMD donors [19]; however, its role in AMD pathogenesis, especially in RPE dedifferentiation, is still largely unknown.…”

Human aqueous humor exosomes

“…Inhibition of MMPs in the trabecular meshwork results in decreased outflow facility (Bradley et al, 1998), so conversely, miR-191 reducing TIMP levels in the trabecular meshwork may result in increased outflow facility. Finally, trabecular meshwork cells are highly phagocytic (Shirato et al, 1989) and the miR-184 we identified in the aqueous humor has been shown to regulate phagocytosis (Murad et al, 2014). …”

“…There is growing interest in serum biomarker tests for ovarian cancer, melanoma, and prostate cancer including the potential role for exosome screening (Li et al, 2009; Logozzi et al, 2009; Lu et al, 2009; Poliakov et al, 2009; Smith et al, 1997; Tavoosidana et al, 2011; Taylor and Gercel-Taylor, 2008). A number of miRNAs, such as miR-34a, miR-130, miR-98, miR-124, miR-204, miR-142, miR-184 and miR-130a, have been shown to contribute to autophagy and phagocytosis (Alexandrov et al, 2013; Murad et al, 2014; Zhai et al, 2013). These are two cellular processes thought to play important roles in the pathogenesis of glaucoma, particularly at the level of the trabecular meshwork (Gasiorowski and Russell, 2009).…”