MicroRNA-17-3p is upregulated in psoriasis and regulates keratinocyte hyperproliferation and pro-inflammatory cytokine secretion by targeting <em>CTR9</em>

Abstract

Psoriasis is a chronic inflammatory skin disease. Although miRNAs are reported to be associated with the pathogenesis of psoriasis, the contribution of individual microRNAs toward psoriasis remains unclear. The miR-17-92 cluster regulates cell growth and immune functions that are associated with psoriasis. miR-17-3p is a member of miR-17-92 cluster; however, its role in dermatological diseases remains unclear. Our study aims at investigating the effects of miR-17-3p and its potential target gene on keratinocytes proliferation and secretion of pro-inflammatory cytokine and their involvement in psoriasis. Initially, we found that miR-17-3p was upregulated in psoriatic skin lesions, and bioinformatic analyses suggested that CTR9 is likely to be a target gene of miR-17-3p. Quantitative reverse-transcriptase PCR and immunohistochemical analysis revealed that CTR9 expression was downregulated in psoriatic lesions. Using dual-luciferase reporter assays, we identified CTR9 as a direct target of miR-17-3p. Further functional experiments demonstrated that miR-17-3p promoted the proliferation and pro-inflammatory cytokine secretion of keratinocytes, whereas CTR9 exerted the opposite effects. Gain-of-function studies confirmed that CTR9 suppression partially accounted for the effects of miR-17-3p in keratinocytes. Furthermore, Western blot revealed that miR-17-3p activates the downstream STAT3 signaling pathway while CTR9 inactivates the STAT3 signaling pathway. Together, these findings indicate that miR-17-3p regulates keratinocyte proliferation and pro-inflammatory cytokine secretion partially by targeting the CTR9, which inactivates the downstream STAT3 protein, implying that miR-17-3p might be a novel therapeutic target for psoriasis.

miRNA implication in the pathogenesis and the outcome of Tunisian endemic pemphigus foliaceus

“…Regarding miR‐17‐5p, our results showed a differential expression of this miRNA in treated patients, with pronounced up‐regulation within chronic patients compared to those developing a mild form. Previously, an up‐regulation of the other arm of miR‐17, miR‐17‐3p, in psoriatic lesions compared to normal skin specimens has been reported 56 . This cutaneous increase in miR‐17 attenuates the SOCS1 gene, leading to an accentuated production of CXCL9 and CXCL10 chemokines and subsequently promoting T‐cell infiltration of the skin 24 .…”

“…Previously, an up-regulation of the other arm of miR-17, miR-17-3p, in psoriatic lesions compared to normal skin specimens has been reported. 56 This cutaneous increase in miR-17 attenuates the SOCS1 gene, leading to an accentuated production of CXCL9 and CXCL10 chemokines and subsequently promoting T-cell infiltration of the skin. 24 In the same context, a recent study identified miR-17 as a key element in the emergence of pathogenic CD4 + T-cells and autoantibody deposition, resulting in skin lesions, an important feature of cutaneous chronic graft-versus-host disease.…”

InflammamiRs in focus: Delivery strategies and therapeutic approaches

“…Ulcerative colitis [34] miR-29 Depletion of the miR-29a/b1 cluster impacts the fibroinflammatory mechanisms AP [35] miR-34 miR-34-LGR4 changed the activity of the NF-κB signaling pathway Chronic wound inflammation [36] Downregulates SIRT1 NEC [37] miR-Increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth [38] miR-206-3p Repressed vascular-specific CXCR4 Atherosclerosis [39] miR-7 Inhibits PTEN and increases the activation of the PI3K/Akt signaling pathway SLE [40] miR-17-3p Activates the downstream STAT3 signaling pathway by targeting CTR9 Psoriasis [41] Anti-inflammatory miRNAs miR-10…”