S1PR3 deficiency alleviates radiation‐induced pulmonary fibrosis through the regulation of epithelial–mesenchymal transition by targeting miR‐495‐3p

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a life-threatening complication of thoracic radiotherapy, which contributes to continued deterioration in pulmonary function.Sphingosine-1 phosphate receptor 3 (S1PR3) has been identified as a crucial molecule in fibrosis. Accumulating evidence indicated that the inhibition of the S1PRs ameliorates fibrogenesis. Thus, this study aims to explore whether S1PR3 participates in RIPF and elucidates the molecular mechanisms underlying S1PR3-modulated epithelial-mesenchymal transition (EMT) in transforming growth factor-β1-induced pulmonary epithelia. A recombinant adeno-associated viral-mediated S1PR3 (AAV-S1PR3) gene therapy analyzed the effect of S1PR3 gene deficiency on the altered histology structure and molecular mechanisms in the lung of mice with whole-lung irradiation. Compared with the AAVnegative control mice, AAV-mediated S1PR3 knockdown in the lung of mice attenuated pulmonary fibrosis induced by the radiation, as indicated by the alleviation of collagen accumulation, lessened histopathological alterations, and the suppression of inflammatory cells infiltration. S1PR3 deficiency reversed the RIPF concomitantly with abrogated EMTrelated protein (α-smooth muscle actin). Consistently, S1PR3-deficient pulmonary epithelia inhibited the EMT process changes and fibrosis formation. Furthermore, S1PR3 was designated as one of the target genes for microRNA-495-3p (miR-495-3p). The inhibition of miR-495-3p promoted the expression of S1PR3 in pulmonary epithelia, whereas the overexpression of miR-495-3p inhibited the S1PR3/SMAD2/3 pathway and suppressed the EMT process. Collectively, miR-495-3p might be a negative regulator of the EMT process in fibrosis formation by inhibiting the targeted S1PR3 gene. These results established a link between the S1PR3 gene, the EMT process, and the fibrosis, suggesting the pharmacological blockage of S1PR3 as a potential therapeutic strategy for RIPF.

Down‐regulated HDAC3 elevates microRNA‐495‐3p to restrain epithelial‐mesenchymal transition and oncogenicity of melanoma cells via reducing TRAF5

“…In addition, we demonstrated that inhibited HDAC3 enhanced miR‐495‐3p to restrict EMT in melanoma by silencing TRAF5. In line with this finding, it has been unveiled that knockdown of HDAC3 constrained EMT of cutaneous squamous cell carcinoma, 23 and a research has clarified that miR‐495‐3p was a negative regulator of EMT in fibrosis formation 24 …”

Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial–mesenchymal transition and inflammation

“…Myofibroblasts derived from epithelial cells via EMT proliferate rapidly and produce the excessed extracellular matrix [5][6][7] . Moreover, a previous study indicated that S1PR3 deficiency alleviated radiation-induced pulmonary fibrosis through the regulation of EMT 8 . β-carboline alkaloids could attenuate BLM-induced pulmonary fibrosis in mice through inhibiting EMT 9 .…”

Hypoxic TAM-derived exosomal miR-155-5p promotes RCC progression through HuR-dependent IGF1R/AKT/PI3K pathway

“…To elucidate the putative mechanism by which TAM-Exos and their transferred miR-155-5p regulated RCC cells functions, we found that miR-155-5p contains a binding site for HuR’s mRNA through bioinformatic analysis. Ago2 is an elementary catalytic constituent of RISC involved in RNA cleavage [ 22 , 24 , 25 ]. To investigate the association between miR-155-5p and HuR mRNA, RIP assays were performed on RCC cells with anti-Ago2 antibody beads (Fig.…”

“…qRT–PCR for analysis of mRNA and miRNA expression was performed as previously described [ 24 ]. The primers were synthesized by RiboBio (Guangzhou, China).…”