Oxidative Stress-Induced circHBEGF Promotes Extracellular Matrix Production via Regulating miR-646/EGFR in Human Trabecular Meshwork Cells.

Wencui Shen,Chengzhi Wang,Bingqing Huang,Juan Gambini

doi:10.1155/2020/4692034

Abstract

Primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss, presents with increased prevalence and a higher degree of clinical severity in the world. Growing evidence has shown that ncRNAs are involved in the fibrotic process, which is thought to be the proegumenal cause of POAG. Here, we screened out a differentially expressed circRNA (named circHBEGF) in human trabecular meshwork cells (HTMCs) under oxidative stress, which is spliced from pre-HBEGF. circHBEGF promotes the expression of extracellular matrix (ECM) genes (fibronectin and collagen I). Further studies revealed that circHBEGF could competitively bind to miR-646 as a miRNA sponge to regulate EGFR expression in HTMCs. Importantly, HBEGF can also activate EGF signaling pathways, through which can transcriptionally activate ECM genes in HTMCs. In summary, this study investigates the functions and molecular mechanisms of oxidative stress-induced circHBEGF in the regulation of ECM production in HTMCs through the miR646/EGFR pathway. These findings further elucidate the pathogenic mechanism and may identify novel targets for the molecular therapy of POAG.

Highlights

Glaucoma is a group of optic neuropathic diseases characterized by progressive and permanent blindness caused by retinal ganglion cell (RGCs) degeneration and their axon loss [1]
Among selected Circular RNA (circRNA), we found that the expression level of hsa_circ_0074241 was intensely higher under oxidative stress (Figure 2(a)). hsa_circ_0074241 was shown to be a circRNA formed by cyclization of exon 2 of pre-HBEGF (Figure 2(b))
We have revealed that SMAD3 and STAT3 participated in transcriptionally regulating extracellular matrix (ECM) genes expression in human trabecular meshwork cells (HTMCs) [12, 16]

Summary

Introduction

Glaucoma is a group of optic neuropathic diseases characterized by progressive and permanent blindness caused by retinal ganglion cell (RGCs) degeneration and their axon loss [1]. It is necessary to explore and clarify the mechanisms of TM changes caused by oxidative stress. Both genetic and epigenetic components play important roles in the occurrence and development of POAG [7,8,9]. Many studies have focused on the effects of noncoding RNAs on its progression, including microRNAs and lncRNAs [10,11,12,13]. We identified the differential expression profile of circRNAs in HTMCs under oxidative stress by microarray analysis. Further studies revealed that circHBEGF can promote ECM production through regulating miR-646/EGFR signaling in HTMCs. The candidate circRNA and its downstream signals may act as novel targets for the treatment of POAG patients

Materials and Methods

Results

Findings

Discussion