Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Poe, Adam J.; Kulkarni, Mangesh; Leszczynska, Aleksandra; Tang, Jie; Shah, Ruchi; Jami‐Alahmadi, Yasaman; Wang, Jason; Kramerov, Andrei A.; Punj, Vasu; Ljubimov, Alexander V.; Saghizadeh, Mehrnoosh

doi:10.3390/cells9102175

Cited by 13 publications

(6 citation statements)

References 74 publications

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“…However, the effect of miR-146a wound healing remains uncertain. Poe et al has reported that several identified miR-146a-targeted pathways are important for corneal epithelial homeostasis, such as EGFR, Notch, anchoring junctions, adherens junctions, TGF-β and inflammation-related signaling 49 . Our present study shows a negative feedback regulation of miR-146a on NF-κB activation and its downstream secreted inflammatory cytokines via IRAK1 and TRAF6 in HCECs, suggesting a potential therapeutic effect on controlling inflammation during DED.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye

Han

Gao

Wang

et al. 2023

Sci Rep

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Inflammation is a key factor in the pathogenesis of dry eye disease (DED). We aimed to investigate the role of microRNA-146a (miR-146a) in regulating corneal inflammation in a mouse model of benzalkonium chloride (BAC)-induced dry eye and the TNF-α-induced NF-κB signaling pathway in human corneal epithelial cells (HCECs). A mouse model of dry eye was established by administering with BAC to BALB/c mice, and the expression of TNF-α, IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) in the corneas of dry eye model mice was significantly increased; this was accompanied by the upregulation of miR-146a and activation of the NF-κB pathway. In vitro, TNF-α induced miR-146a expression in HCECs, while the NF-κB inhibitor SC-514 reduced the expression of miR-146a. Overexpression of miR-146a decreased the expression of IRAK1 and TRAF6, which have been identified as targets of miR-146a. Furthermore, overexpression of miR-146a suppressed NF-κB p65 translocation from the cytoplasm to the nucleus. Moreover, overexpression of miR-146a attenuated the TNF-α-induced expression of IL-6, IL-8, COX2 and intercellular adhesion molecule 1 (ICAM1), while inhibition of miR-146a exerted the opposite effect. Our results suggest that miR-146a mediates the inflammatory response in DED. MiR-146a negatively regulates inflammation in HCECs through the IRAK1/TRAF6/NF-κB pathway, and this may serve as a potential therapeutic approach for the treatment of DED.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye

Han

Gao

Wang

et al. 2023

Sci Rep

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“…MiR-146a was found hyper-expressed in patients with Sjogren’s syndrome, a condition characterized by dry eye, and in Sjogren-prone mice as well [ 40 , 41 ]. In addition, Movahedan et al [ 42 ] described a Notch1 -mediated decrease in early-stage corneal wound healing, and a recent study by using human primary limbal epithelial cells [ 43 ] demonstrated that miR-146a increased Notch 1 by Numb downregulation. In accordance, both Targetscan human v7.2 ( ; accessed 6 October 2021) and miRDB ( ; accessed 6 October 2021) databases report miR-146a-5p/ Numb interaction, and previous studies on other cell types demonstrated the miR-146a-mediated Numb downregulation as well [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway

Compagnoni

Zelli

Bianchi

et al. 2022

IJMS

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Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. Conclusions. MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications.

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“…In this regard, the insertion of specific miRNAs has been shown to promote corneal regeneration by increasing the expression of c-MET and inhibiting that of cathepsin F and MMP-10, thus accelerating tissue healing in diabetic patients [ 118 ]. In addition, miRNA 146-α can modulate corneal regeneration and stem reservoir maintenance [ 119 , 120 ] and it has been shown that its overexpression can alter normal repair functions in diabetic corneas [ 121 , 122 ]. The main studies regarding the role of miRNAs in corneal regeneration are summarized in Table 2 .…”

Section: Subcellular Therapiesmentioning

confidence: 99%

Corneal Epithelial Regeneration: Old and New Perspectives

Nuzzi

Giuffrida

Luccarelli

et al. 2022

IJMS

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Corneal blindness is the fifth leading cause of blindness worldwide, and therapeutic options are still often limited to corneal transplantation. The corneal epithelium has a strong barrier function, and regeneration is highly dependent on limbal stem cell proliferation and basement membrane remodeling. As a result of the lack of corneal donor tissues, regenerative medicine for corneal diseases affecting the epithelium is an area with quite advanced basic and clinical research. Surgery still plays a prominent role in the treatment of epithelial diseases; indeed, innovative surgical techniques have been developed to transplant corneal and non-corneal stem cells onto diseased corneas for epithelial regeneration applications. The main goal of applying regenerative medicine to clinical practice is to restore function by providing viable cells based on the use of a novel therapeutic approach to generate biological substitutes and improve tissue functions. Interest in corneal epithelium rehabilitation medicine is rapidly growing, given the exposure of the corneal outer layers to external insults. Here, we performed a review of basic, clinical and surgical research reports on regenerative medicine for corneal epithelial disorders, classifying therapeutic approaches according to their macro- or microscopic target, i.e., into cellular or subcellular therapies, respectively.

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Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Cited by 13 publications

References 74 publications

MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye

MicroRNA-146a negatively regulates inflammation via the IRAK1/TRAF6/NF-κB signaling pathway in dry eye

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway

Corneal Epithelial Regeneration: Old and New Perspectives

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