A novel molecular mechanism of microRNA‐21 inducing pulmonary fibrosis and human pulmonary fibroblast extracellular matrix through transforming growth factor β1–mediated SMADs activation

Abstract

Pulmonary fibrosis (PF), characterized by the destruction of lung tissue architecture and the abnormal deposition of extracellular matrix (ECM) proteins, currently has no satisfactory treatment. The role of microRNA (miR)-21 in PF has been reported; the current study attempted to investigate a novel molecular mechanism by which miR-21 exerted its function. Consistent with previous studies, miR-21 inhibition reduced ECM protein levels in bleomycin (BLM)-induced mouse model of PF. In human pulmonary fibroblast (IMR-90), miR-21 inhibition reduced transforming growth factor β1 (TGFβ1)-induced ECM protein expression. Regarding a novel molecular mechanism, TGFβ1 combined with TGFβ1 receptor 1 (TGFβ1RI) to activate SMAD2/3, promote SMAD4 nucleus transformation, and thus regulate miR-21 expression and ECM. SMAD3 and SMADs complex could bind to the promoter region of miR-21 to promote miR-21 expression. In conclusion, miR-21 exerts promotive effects on BLM-induced PF and TGFβ1-induced ECM in IMR-90; TGFβ1 combines with TGFβ1RI to activate SMAD2/3, promote SMAD4 nucleus transformation, promote miR-21 expression, and thus to promote BLM-induced PF and TGFβ1-induced ECM in IMR-90 cells.

The Smad2/3/4 complex binds miR‐139 promoter to modulate TGFβ‐induced proliferation and activation of human Tenon's capsule fibroblasts through the Wnt pathway

“…Subsequently, downstream Smad2 and 3 can be phosphorylated by the activated complex to form a Smad4-containing compound that is transferred to the nucleus to initiate gene transcription and modulate cellular biological processes (Massagué, promoter region of miR-139 to inhibit its transcription activity, most possibly by Smad4 binding to the miR-139 promoter. Our observation is consistent with a previous study indicating that TGFβ1 binds to TGFβ1RⅠ to activate Smad2/3, promotes SMAD4 nucleus transformation, promote miR-21 transcription, thereby promoting bleomycin-induced pulmonary fibrosis and TGFβ1-induced ECM synthesis in IMR-90 cells (Zhou et al, 2018).…”

The Role of miRNAs in Idiopathic Pulmonary Fibrosis

“…MicroRNAs (miRNAs) are short single-stranded RNA molecules of [19][20][21][22][23][24][25] nucleotides in length that mediate posttranscriptional gene silencing of target genes [5]. MiRNAs have been recognized as a distinct class of small regulatory RNAs in multiple species that regulate a wide variety of functions such as cell proliferation, differentiation, apoptosis, stress response, and immune response [6][7][8].…”

“…Profiling of miRNAs in the lung tissue from IPF patients was performed by different groups [18][19][20][21][22]. In IPF lungs, the expression of miR-21 and miR-155 was increased, whereas the expression of let-7a, miR-29, miR-30, and miR-101 was decreased [23][24][25]. MiR-21 expression was increased in the serum of IPF patients, and its levels correlated with a decrease in lung function [26].…”

“…The expression of miR-21 is increased in the lungs of mouse IPF models and of patients with IPF [19]. In mouse IPF models, miR-21 inhibition by lentiviruses encoding anti-miR-21 suppressed morphological markers of pulmonary fibrosis compared with controls [23]. TGF-β1 is the most important profibrogenic cytokine, which increases the expression of miR-21 through SMAD2/3/4 in lung fibroblasts [19] [66].…”

“…TGF-β1 is the most important profibrogenic cytokine, which increases the expression of miR-21 through SMAD2/3/4 in lung fibroblasts [19] [66]. MiR-21 inhibition inversely regulates TGF-β1-induced ECM protein expression in human pulmonary fibroblast cell lines [23]. Smad7, which inhibits the proliferation of interstitial fibroblasts, is a direct target of miR-21 and negatively correlates with miR-21 in pulmonary fibroblasts [19].…”