Abstract
Diminished microRNA-29b levels have recently been revealed to provoke increased expression and accumulation of extracellular matrix molecules, such as collagens in fibrotic remodeling. Subsequently, the aim of this study was to find out whether microRNA-29b might also regulate human xylosyltransferase (XT)-I expression. XT-I has been characterized previously as a fibrosis biomarker catalyzing the key step of proteoglycan biosynthesis. While we demonstrate that XYLT1 is neither a target of microRNA-29b identified in silico nor a direct 3′ untranslated region binding partner of microRNA-29b, transfection of normal human dermal fibroblasts with microRNA-29b inhibitor strongly increased XYLT1 mRNA expression and XT activity. Combined results of the target prediction analysis and additional transfection experiments pointed out that microRNA-29b exerts indirect influence on XT-I by targeting the transcription factor specificity protein 1 (Sp1). We could confirm our hypothesis due to the decrease in XYLT1 promoter activity after Sp1 binding site mutation and the approval of occupancy of these binding sites by Sp1 in vitro. Taken together, a hitherto unidentified pathway of XT-I regulation via microRNA-29b/Sp1 was determined in this study. Our observations will facilitate the understanding of complex molecular fibrotic pathways and provide new opportunities to investigate microRNA-based antifibrotic tools.
Highlights
MicroRNAs are small endogenous noncoding RNA molecules, which consist of 18 to 25 nucleotides
Gene expression analysis using a miRNA polymerase chain reaction (PCR) array was performed to verify this in our myofibroblast cultivation system
We found that miRNA-29b expression was 0.4-fold diminished in normal human dermal fibroblasts (NHDF) treated with transforming growth factor-β1 (TGF-β1) compared to controls
Summary
MicroRNAs (miRNAs) are small endogenous noncoding RNA molecules, which consist of 18 to 25 nucleotides. Many diseases have been associated with abnormal miRNA expression profiles, so that miRNAs are used as biomarkers, and handled as potential therapeutic targets to exert influence on dysregulated molecular pathways[4]. Zhou et al.[10] found that the miRNA-21 level in the serum of systemic sclerosis (SSc) is highly induced, while they identified 21 miRNAs which are differentially expressed in SSc skin tissues. In line with these observations, an attenuation of unilateral ureteral obstruction-induced renal fibrosis after blocking miRNA-21 in vivo was reported. A miRNA-145 deficiency was further evaluated to be protective against bleomycin-induced lung fibrosis in a mouse model[12]
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