Abstract
Transforming growth factor-β (TGF-β) is a potent cytokine that promotes the development of fibrogenic cells, stimulates the expression of fibrosis-related genes, and consequently results in hepatic fibrogenesis. The involvement of miRNAs in this process remains largely unknown. We showed that miR-122 was substantially expressed in hepatic stellate cells (HSCs) and fibroblasts, the major sources of fibrogenic cells in liver tissues. Notably, exposure to TGF-β led to significant downregulation of miR-122. Furthermore, reintroduction of miR-122 suppressed TGF-β-induced expression of fibrosis-related genes, including alpha smooth muscle actin (α-SMA), fibronectin 1 (FN1) and α1 type I collagen (COL1A1), in HSCs and fibroblasts. Subsequent mechanism investigations revealed that miR-122 directly inhibited FN1 expression by binding to its 3'-untranslated region and indirectly reduced the transcription of α-SMA and COL1A1 by inhibiting the expression of serum response factor (SRF), a key transcription factor that mediated the activation of fibrogenic cells. Further in vivo studies disclosed that intravenous injection of miR-122-expressing lentivirus successfully increased miR-122 level and reduced the amount of collagen fibrils, FN1 and SRF in the livers of CCl4-treated mice. These findings disclose a novel TGF-β-miR-122-FN1/SRF signaling cascade and its implication in hepatic fibrogenesis, and suggest miR-122 as a promising molecular target for anti-fibrosis therapy.
Highlights
Hepatic fibrosis is an outcome of the pathological response to chronic liver injuries and is characterized by the increased deposition and altered composition of extracellular matrix (ECM) [1]
Subsequent mechanism investigations revealed that miR-122 directly inhibited fibronectin 1 (FN1) expression by binding to its 3’-untranslated region and indirectly reduced the transcription of α-SMA and COL1A1 by inhibiting the expression of serum response factor (SRF), a key transcription factor that mediated the activation of fibrogenic cells
ECM is changed from a type IV collagen-rich composition to a type I collagen- and fibronectin 1 (FN1)rich composition, which distorts the architecture of the liver, and leads to hepatic cirrhosis and hepatocellular cancer (HCC) [1]
Summary
Hepatic fibrosis is an outcome of the pathological response to chronic liver injuries and is characterized by the increased deposition and altered composition of extracellular matrix (ECM) [1]. The activation of fibrogenic cells is critical for hepatic fibrosis. In response to chronic liver injuries, the expression and secretion of transforming growth factor-β (TGF-β) significantly increases. TGF-β is the most potent fibrogenic cytokine that activates the HSCs and fibroblasts to express fibrosis-related genes, including alpha smooth muscle actin (α-SMA), FN1 and α1 type I collagen (COL1A1), and promotes www.impactjournals.com/oncotarget hepatic fibrogenesis [1, 2]. Α-SMA, besides as a key molecular marker for the activated fibrogenic cells, promotes contractile force and ECM stiffness [1, 2]. Great efforts have been dedicated to unravel the molecular mechanisms underlying liver fibrogenesis, whether microRNAs (miRNAs) may regulate liver fibrogenesis is still poorly understood
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