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BACKGROUND The hyper-accumulation of extracellular matrix (ECM) is the leading cause of hepatic fibrosis, and TGF-β-induced activation of hepatic stellate cells (HSCs) is the central event of hepatic fibrosis pathogenesis. The deregulation and dysfunction of miRNAs in hepatic fibrosis have been reported previously. AIMS To identify miRNA(s) playing a role in HSC activation and the underlying mechanism. METHODS We analyzed online microarray expression datasets from Gene Expression Omnibus (GEO) for differentially expressed miRNAs in hepatic fibrosis-related disease liver tissues, examined the specific effects of the candidate miRNA on TGF-β-induced HSC activation, and screened for the targets of the candidate miRNA in the TGF-β/SMAD signaling. Then, the predicted miRNA-mRNA binding, the specific effects of the target mRNA, and the dynamic effects of miRNA and mRNA on TGF-β-induced HSC activation were investigated. RESULTS The miR-503 expression was upregulated in TGF-β-activated HSCs. miR-503 overexpression enhanced, while miR-503 inhibition attenuated TGF-β-induced HSC proliferation and ECM accumulation in HSCs. miR-503 targeted SMAD7 to inhibit SMAD7 expression. SMAD7 knockdown also aggravated TGF-β-induced HSC proliferation and ECM accumulation in HSCs. The effects of miR-503 overexpression on TGF-β-induced HSC activation were partially reversed by SMAD7 overexpression. In CCl4-induced hepatic fibrosis model in rats, miR-503 overexpression aggravated, whereas SMAD7 overexpression improved CCl4-induced fibrotic changes in rats\' liver tissues. The effects of miR-503 overexpression on CCl4-induced fibrotic changes were partially reversed by SMAD7 overexpression. CONCLUSION miR-503 acts on HSC activation and hepatic fibrosis through SMAD7. The miR-503/SMAD7 axis enhances HSC activation and hepatic fibrosis through the TGF-β/SMAD pathway.
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10.1007/s10620-020-06460-7
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Digestive_diseases_and_sciences
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MicroRNA-503 Targets Mothers Against Decapentaplegic Homolog 7 Enhancing Hepatic Stellate Cell Activation and Hepatic Fibrosis.
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