Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Abstract

The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl 4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl 4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury

“…ASTEX were deficient in proinflammatory and profibrotic miRs including miR-199a, miR-143, miR-382, and miR-134 ( Figure 3C ). MiR-199a promotes fibrosis through suppression of caveolin and induction of the TGFβ pathway ( Yang et al, 2020 ). MiR-143 also promotes fibrosis through targeting sprouty RTK signaling antagonist 3 (Spry3) to activate the p38-ERK-JNK signaling axis ( Li et al, 2019 ).…”

MiR-130a-3p Alleviates Liver Fibrosis by Suppressing HSCs Activation and Skewing Macrophage to Ly6Clo Phenotype

“…Up to date, accumulating evidences have suggested that miRNAs play important roles and might be regarded as a potential therapeutic target in regulating the progression and development of several liver diseases (13)(14)(15)(16). Previous reports have demonstrated that there were increased levels of miR-130a-3p in myocardial injury, and downregulation of miR-130a-3p could remarkably relieve hypoxia-induced inflammation and inhibit the expression of fibrosis-related protein (17).…”

Integrated Analysis of Hepatic miRNA and mRNA Expression Profiles in the Spontaneous Reversal Process of Liver Fibrosis

“…Interestingly, the miRNAs that regulate HSCs phenotype were consistently reversed with a concomitant decrease in hepatic ECM deposition. miRNAs that activate HSCs (miR-199a-3p and miR-214-3p) were significantly suppressed (Ma et al, 2018;Yang et al, 2020), while those restrain the proliferation and activation of HSCs (miR-378a-3p, miR-139-5p, miR-455-3p, and miR-193a-3p) were remarkably increased during the fibrosis regression (Hyun et al, 2016;Ju et al, 2019;Wei et al, 2019;He et al, 2021). Among the differentially (mmu-miR-1843a-5p, mmu-miR-193a-5p, mmu-miR-194-2-3p, and mmu-miR-30c-2-3p) and their target genes.…”