STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop affects psoriasis pathogenesis via regulating human keratinocyte proliferation

Abstract

Psoriasis is a chronic immune-mediated inflammatory dermatosis. STAT3 has been considered a critical regulator of psoriasis pathogenesis due to its role in inflammation and immune responses. Furthermore, alongside non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs, STAT3 also plays a critical role in psoriasis pathogenesis. Two sets of online microarray profiles (GSE50790 and GSE13355) were subsequently downloaded and analyzed to search for lncRNAs upregulated in psoriasis lesion tissues. The expression of lncRNA SH3PXD2A-AS1 could be remarkably upregulated in psoriasis specimens. SH3PXD2A-AS1 silence was found to suppress HaCaT cell proliferation and promote HaCaT cell apoptosis significantly. Meanwhile, SH3PXD2A-AS1 silence significantly increased cleaved-caspase-3 protein levels and inhibited S100A7, TNF-α, IL-6, p-STAT3, STAT3, CyclinD1, and survivin protein levels. Moreover, the expression of miR-125b could be substantially decreased within psoriasis lesion tissue samples, while miR-125b could negatively regulate the SH3PXD2A-AS1 and STAT3 expression. As predicted by an online tool and validated by luciferase reporter and RIP assays, miR-125b was found to bind to SH3PXD2A-AS1 and STAT3 3′UTR directly; SH3PXD2A-AS1 competed with 3′UTR of STAT3 for miR-125b binding to counteract miR-125b-mediated suppression of STAT3. STAT3 is known to activate the transcription of SH3PXD2A-AS1 through the targeting of its promoter region. It consequentially forms a regulatory feedback loop promoting SH3PXD2A-AS1 expression affecting HaCat cell proliferation and apoptosis. A novel STAT3 related mechanism whereby STAT 3/ SH3PXD2A-AS1/ miR-125b/STAT3 positive feedback loop which could potentially affect the pathogenesis of Psoriasis has been established.