MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1

Abstract

Abstract. Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. IRS-1 was predicted to be the target gene of microRNA-126 (miR-126). The present study was designed to illustrate the involvement of miR-126 in the regulation of DR via targeting IRS-1. The present study revealed that the expression of miR-126 was significantly decreased while IRS-1 expression was increased in endothelial cells (ECs) and retinal pericytes (RPs) from a DR mouse model compared with healthy controls. Furthermore, a luciferase reporter assay confirmed the interaction between miR-126 and IRS-1. Following transfection with anmiR-126 mimic or miR-126 inhibitor, overexpression of miR-126 was demonstrated to suppress the invasion and viability of ECs and RPs and to inhibit the IRS-1 and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway protein expression levels, with inhibition of miR-126 leading to reverse results. Furthermore, transfection with small interfering RNA targeting IRS-1 altered the miR-126-induced effects observed in ECs, indicating that miR-126 may suppress angiogenesis in DR via inhibition ofIRS-1 expression. Taken together, the results of the present study suggested that miR-126 affected the expression of IRS-1, resulting in downregulated expression of PI3K/Akt pathway proteins, and also suppressed cell invasion and viability. These results may provide a potential therapeutic strategy for DR.

Joint action of miR‐126 and MAPK/PI3K inhibitors against metastatic melanoma

“…Finally, as an insulin feedback was reported to limit the efficacy of PI3K inhibition in several tumor models (Hopkins et al ., ), we checked for the effects of the combined PIK‐75 plus vemurafenib therapy on the expression of the IRS‐1. IRS‐1, a key molecule in signal transduction between the insulin receptor and PI3K, was demonstrated to be a target gene of miR‐126 in different cancers (Fang et al ., ). Expression studies, besides confirming IRS‐1 down‐regulation in miR‐126‐transduced A375M melanoma compared with TripZ control cells, showed the strong induction of IRS‐1 in PIK‐75 + vemurafenib cotreated A375M cells, a result suggestive of the association of its activation with drug resistance.…”

“…In tumor samples, we showed reduced proliferation and increased apoptosis as indicated by Ki67 and caspase 3 modulations. According to recently published data (Hopkins et al ., ), miR‐126 also appeared able to disrupt the insulin regulatory loop by reducing the expression of the key factor IRS‐1, reported as a target gene of miR‐126 (Fang et al ., ). In addition, proteomic analysis showed the effectiveness of miR‐126 action on the mTOR pathway, one of the key controllers of cancer metabolism (Fig.…”

MicroRNAs: Potential Targets in Diabetic Retinopathy

“…Notably, in the same individuals, only a few circulating miRNAs were detected in vitreous compared with serum [10]. In ▶ table 1, we have summarized miR-126 [11,12], miR-211 [13], miR-93 [14][15][16], miR-122 [17], miR-221 [18], miR-27b and miR-320a [8], miR-150-5p, miR-21-3p and miR-30b-5p [19] as biomarkers in DR over the past 5 years. At the same time, we have focused on miRNAs in vitreous humor (VH) of DR, such as miR-126 [20], miR-19a and 27a [21], miR-29a [22,23], miR-93 and 20a [21], and miR-200b [24] in ▶ table 2.…”

Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

“…Moreover, it has been demonstrated that insulin receptor substrate 1 (IRS-1) is a target gene of miR-126 in endothelial cells and retinal pericytes in an animal model of DR. Furthermore, the interaction between them downregulates the expression of PI3K/Akt pathway proteins and negatively influences the viability and invasion of endothelial cells and retinal pericytes isolated from a mice model of DR [150]. The PI3K/Akt pathway is crucial for a long-term upregulation of VEGF, which is an angiogenic factor involved in the pathogenesis of DR.…”