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?:abstract
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BACKGROUND: The hyper-accumulation of extracellular matrix (ECM) is the leading cause of hepatic fibrosis, and TGF-ß-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-ß-induced HSC activation, and screened for the targets of the candidate miRNA in the TGF-ß/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-ß-induced HSC activation were investigated. RESULTS: The miR-503 expression was upregulated in TGF-ß-activated HSCs. miR-503 overexpression enhanced, while miR-503 inhibition attenuated TGF-ß-induced HSC proliferation and ECM accumulation in HSCs. miR-503 targeted SMAD7 to inhibit SMAD7 expression. SMAD7 knockdown also aggravated TGF-ß-induced HSC proliferation and ECM accumulation in HSCs. The effects of miR-503 overexpression on TGF-ß-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-ß/SMAD pathway.
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