The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

Abstract

Background: MicroRNA-21 is important in hepatic fibrosis development, but the mechanism is unclear. Results: MicroRNA-21 is predominantly up-regulated in activated hepatic stellate cells and could form a double negative feedback loop that links fibrogenic machinery. Conclusion:The microRNA-21-mediated loop is a main driving force for hepatic fibrosis progression. Significance: It suggests a mechanism for how microRNA-21 contributes to hepatic fibrosis.Sustained activation of hepatic stellate cells (HSCs) leads to hepatic fibrosis, which is characterized by excessive collagen production, and for which there is no available drug clinically. Despite tremendous progress, the cellular activities underlying HSC activation, especially the driving force in the perpetuation stage, are only partially understood. Recently, microRNA-21 (miR-21) has been found to be prevalently up-regulated during fibrogenesis in different tissues, although its detailed role needs to be further elucidated. In the present study, miR-21 expression was examined in human cirrhotic liver samples and in murine fibrotic livers induced by thioacetamide or carbon tetrachloride. A dramatic miR-21 increase was noted in activated HSCs. We further found that miR-21 maintained itself at constant high levels by using a microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) feedback loop. Disrupting this loop with miR-21 antagomir or AP-1 inhibitors significantly suppressed fibrogenic activities in HSCs and ameliorated liver fibrosis. In contrast, reinforcing this loop with small interfering RNA (siRNA) against PDCD4 promoted fibrogenesis in HSCs. Further analysis indicated that the up-regulated miR-21 promoted the central transforming growth factor-␤ (TGF-␤) signaling pathway underlying HSC activation. In summary, we suggest that the miR-21/PDCD4/AP-1 autoregulatory loop is one of the main driving forces for hepatic fibrosis progression. Targeting this aberrantly activated feedback loop may provide a new therapeutic strategy and facilitate drug discovery against hepatic fibrosis.Hepatic fibrosis is a wound healing process in response to chronic liver injuries that leads to unbalanced extracellular matrix (ECM) 3 deposition and resolution. The persistent activation of wound healing responses causes quantitative and qualitative changes in the ECM components and could finally distort liver parenchyma and vascular architecture, which could impair liver function and potentially lead to liver failure and hepatocellular carcinoma. Following liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells that are characterized by the expression of smooth muscle ␣-actin (␣-SMA) and enhanced production of ECM (1). Despite the tremendous progress in understanding the mechanisms during fibrogenesis, the driving force underlying the persistent fibrogenic activities is still only partially understood.Extensive studies have suggested the central role of feedback networks in dictating disease progressi...

Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells

“…The upregulation of miR-21 is also observed in patients with idiopathic pulmonary fibrosis and in human fibrotic livers. 21,22 In the kidney, various studies have suggested that miR-21 is crucial in TGF-b-stimulated renal fibrosis. The levels of miR-21 could be increased Figure 4 Effects of SphK1/S1P and miR-21 on ECM proteins and EMT marker molecules expression.…”

“…13 The miR-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) autoregulatory loop is one of the main driving forces for hepatic fibrosis and myocardial fibrosis. 21 Besides, MMP9/TIMP1, silencing metabolic pathways, and Smad 7 signaling might be also implicated in the miR-21-mediated fibrosis. 14,15 However, the specific mechanism and regulatory network that involved in the modulation of miR-21 to fibrotic dysfunction of kidney is not well defined and is the next focus point in our subsequent study.…”

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

“…[25] Clinical expression data for PSCs have not been published yet, but for HSCs and liver fibrosis several investigations are available. The hepatic contents of miR-21 [27,28], miR-33a [29] and miR200b [30] were significantly increased in liver specimens from human patients with liver fibrosis as compared to normal patients. Upregulation was also identified for miR-199a-5p/199a-3p and miR-221/222 in hepatitis C induced liver fibrosis in a fibrosis progression-dependent manner.…”

“…This appears to be based on a miR-21 feedback loop with these signaling pathways promoting fibrogenesis and the TGF-β signaling pathway underlying HSC activation. [28] MiR-145 is inducible by treatment with TGF-β leading to enhanced α-SMA expression in normal gastric fibroblasts and CAFs. [24] MiR-27a/b-transfected normal fibroblast showed α-SMA expression and increased production of TGF-β as typical characteristics of CAFs.…”

“…This miR may be an important factor in "activating" NFs into CAFs and its expression is mostly confined to cancer stroma [16,4]. Via direct targeting miR-21 is a negative regulator of programmed cell death protein 4/activation protein-1 (PDCD4/AP-1) in cancer cells [26] and HSCs [28]. This appears to be based on a miR-21 feedback loop with these signaling pathways promoting fibrogenesis and the TGF-β signaling pathway underlying HSC activation.…”