AP-1 transcription factor decoy reduces the TGF-β1-induced cell growth in scleroderma fibroblasts through inhibition of cyclin E

Abstract

The transforming growth factor-ß (TGF-ß) signaling pathway plays a key role in the abnormal accumulation of type I and III collagen of scleroderma. Activator protein-1 (AP-1) is a key regulatory protein in TGF-ß1-induced type I collagen synthesis. However, it is largely unknown whether AP-1 is involved in the cell proliferation of fibroblasts in scleroderma. In this study, we investigated the effects of the AP-1 oligo-deoxynucleotide (ODN) decoy on TGF-ß1induced cell growth in scleroderma fibroblasts. To investigate the inhibition of AP-1 ODN decoy on the growth rates of scleroderma fibroblasts through the regulation of cell cycle regulatory proteins, we transfected the AP-1 ODN decoy on scleroderma fibroblasts and analyzed the cell cycle regulatory proteins by RT-PCR and Western blot analysis. We found that the growth rates of normal fibroblasts and scleroderma fibroblasts showed similar rates. It is noteworthy that the scleroderma fibroblasts grew more rapidly than normal fibroblasts in the presence of TGF-ß1. Moreover, the transfection of AP-1 decoy ODN into scleroderma fibroblasts resulted in the down-regulation of the growth rates by the down-regulation of cyclin E. These results collectively suggest that AP-1 ODN decoy can down-regulate the growth rates of scleroderma fibroblasts, thus implying that AP-1 ODN decoy is a promising therapeutic tool for overcoming scleroderma.

MicroRNA array analysis of microRNAs related to systemic scleroderma

“…These six miRNAs are hsamiR-206, hsa-miR-133a, hsa-miR-125b, hsa-miR-140-5p, hsa-miR-23b and hsa-let-7 g, and they regulate hundreds of target genes. Some of the target genes are involved in SSc pathogenesis, particularly the targets of hsa-miR-206, which regulates about 516 target genes, including 15 genes [21][22][23][24][25][26]. The upregulation of these targets in SSc skin lesions and blood, and in cell or mouse On the whole, the target genes of the differentially expressed miRNAs involved in SSc pathology play important roles in many processes including the cell cycle, cell proliferation, differentiation, apoptosis, cell signaling, inflammation, fibrosis and SSc development.…”

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

“…Transcription factor decoy oligonucleotides have been used to modulate gene expression in vitro and in vivo . Decoys for NF-kB (29,30,55–58), STAT3 (59,60), p53 (61), E2F (62,63) and AP-1(64) have been previously proposed. Our decoys are mimics of a G4-DNA structure that can be formed in NHE of the human KRAS promoter.…”

Oxidative stress and glutathione in TGF-β-mediated fibrogenesis

“…One of the major mechanisms by which TGF-β induces fibrosis is stimulating fibroblast proliferation and activation. TGF-β has been shown to stimulate the proliferation and activation of fibroblasts originating from different organ systems [136–141] and ROS/RNS play critical role in this process [98, 103]. Cucoranu et al reported that TGF-β treatment stimulated the expression of Nox4 and alpha smooth muscle actin (α-SMA), a myofibroblast marker, in primary human cardiac fibroblasts while knockdown of Nox4 by siRNA reduced TGF-β-stimulated production of ROS and α-SMA mRNA expression, suggesting that ROS mediate TGF-β-induced differentiation of cardiac fibroblasts to myofibroblasts [98].…”