c-Jun-mediated microRNA-302d-3p induces RPE dedifferentiation by targeting p21Waf1/Cip1

Abstract

Dedifferentiation of retinal pigment epithelium (RPE) cells and choroidal neovascularization (CNV) contributes to the pathogenesis of age-related macular degeneration (AMD). MicroRNAs (miRNAs) have crucial roles in AMD onset and progression. We thus aim to investigate the effects of miRNAs on RPE dedifferentiation and endothelium cell (EC) behavior, and analyze its downstream pathways. We have previously identified miR-302d-3p as the most downregulated miRNA signature along with RPE differentiation. Herein, in vitro study supported that miR-302d-3p induces RPE dedifferentiation typified by reduction of RPE characteristic markers, interrupts its phagocytosis, and promotes its migration, proliferation, and cell-cycle progression. c-Jun was identified as a potential upstream transcript factor for MIR302D, which might modulate RPE function by regulating miR-302d-3p expression. P21Waf1/Cip1, a cyclin-dependent kinase inhibitor encoded by the CDKN1A gene, was identified as a downstream target of miR-302d-3p. Our data suggested that p21Waf1/Cip1 could promote RPE differentiation, and inhibit its proliferation, migration, and cell-cycle progression. We also demonstrated that miR-302d-3p suppresses RPE differentiation through directly targeting p21Waf1/Cip1. In addition, the miR-302d-3p/CDKN1A axis was also involved in regulating tube formation of ECs, indicating its potential involvement in CNV formation. Taken together, our study implies that miR-302d-3p, regulated by c-Jun, contributes to the pathogenesis of both atrophic and exudative AMD. MiR-302d-3p promotes RPE dedifferentiation, migration, proliferation and cell-cycle progression, inhibits RPE phagocytosis, and induces abnormal EC behavior by targeting p21Waf1/Cip1. Pharmacological miR-302d-3p inhibitors are prospective therapeutic options for prevention and treatment of AMD.

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

“…CDKN1A is involved in RPE differentiation, proliferation, migration, and cell-cycle progression [ 112 ]. As such, CDKN1A plays a role in the ageing process of RPE and hence in AMD [ 113 ]. SERPINA1 is serine protease inhibitor and has a role in prevention against tissue destruction [ 114 ].…”

Cardiac Extracellular Vesicles (EVs) Released in the Presence or Absence of Inflammatory Cues Support Angiogenesis in Different Manners

“…Unstimulated CardAP-EVs carried a higher copy number of miRNA302d-3p in comparison to cytokine stimulated CardAP-EVs, which was additionally verified by qPCR. Others have shown that this miRNA stimulated HUVECs to release more VEGF as well as to increase their tube formation capabilities in comparison to untreated controls [41]. Additionally, this group demonstrated that the pro-angiogenic potential of miRNA302-3p was abolished in inhibition experiments using siRNA and other inhibitors of the involved pathway.…”

Emerging roles of non‐coding RNAs in retinal diseases: A review

“…For example, miR-302d-3p triggers RPE dedifferentiation by targeting p21Waf1/Cip1. 57 miR-184 promotes RPE differentiation by inhibiting the AKT2/mTOR signalling pathway. 58 miR-132 was shown to be involved in brain derived neurotrophic factor -mediated retinal axon branching via downregulation of p250GAP.…”

“…The function of other miRNAs in the retina has also been studied. For example, miR‐302d‐3p triggers RPE dedifferentiation by targeting p21Waf1/Cip1 57 . miR‐184 promotes RPE differentiation by inhibiting the AKT2/mTOR signalling pathway 58 .…”