MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7

Abstract

A considerable amount of research has focused on the roles of microRNAs (miRNA) in the pathophysiology of liver fibrosis in view of their regulatory effects on hepatic stellate cell (HSC) functions, including proliferation, differentiation, and apoptosis. Recently, miR-17-5p was shown to promote cell proliferation and migration in liver. Transforming growth factor-β1 (TGF-β1) has been characterized as the master fibrogenic cytokine that stimulates HSC activation and promotes progression of liver fibrosis. The issue of whether miR-17-5p plays a role in TGF-β1-induced hepatic fibrogenesis remains to be established. In this study, we demonstrated a dose-/time-dependent increase in miR-17-5p expression in TGF-β1-treated HSCs. Enhanced miR-17-5p expression was additionally observed in CCl 4 -induced rat liver fibrosis. Inhibition of miR-17-5p led to suppression of HSC proliferation induced by TGF-β1 without affecting cellular apoptosis. Notably, miR-17-5p was significantly associated with TGF-β1-induced expression of type I collagen and α-SMA in HSC. Furthermore, Smad7, a negative regulator of the TGF-β/Smad pathway, was confirmed as a direct target of miR-17-5p. Serum miR-17-5p levels were significantly higher in patients with cirrhosis, compared to healthy controls. Our results collectively indicate that miR-17-5p promotes HSC proliferation and activation, at least in part, via reduction of Smad7, supporting its potential utility as a novel therapeutic target for liver fibrosis.

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

“…siRNAs and miRNAs have been extensively investigated in the past 10 years. [4][5][6] MicroRNA-101 (miR-101) is one of the most studied miRNAs in liver fibrosis. Upregulation of miR-101 inhibits liver fibrosis by targeting the type I TGF-b receptor.…”

HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis

“…5 Emerging evidence has revealed that miRNAs are implicated in HSC activation and thereby regulate liver fibrosis. [6][7][8][9] For example, Wang et al reported that miR-29b prevents liver fibrosis by suppressing HSC activation and inducing cell apoptosis via targeting PI3K/ AKT pathway. 3 Our previous study found that curcumin upregulates miR-29b expression, leading to the silencing of DNA methyltransferase 3b (DNMT3b) and the loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) methylation, which contributes to suppression of activated HSCs.…”

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

“…[35] Hepatic expression levels of miR-199a, miR-199a*, miR-200a, and miR-200b were positively associated with progression of liver fibrosis. [30,36] In liquid biopsies, levels of miR-17-5p [37], miR-21 [27], miR-33a [29] and miR-181b but not miR181a expression [38] were higher in fibrotic than in normal patients. In addition, miR-133a serum levels were increased in patients with chronic liver disease and indicative for the presence and progression of liver cirrhosis.…”

“…MiR-122 overexpression also led to decreased collagen maturation and ECM production [46] whereas miR-126 [42] and miR-17-92 cluster members [37] induced type 1 collagen expression. Reduced expression of miR-335 during HSC activation promotes their cell migration via targeting tenascin-C and enhanced expression of α-SMA and type 1 collagen.…”

“…Its inhibition also led to suppression of HSC proliferation induced by TGF-β1 without affecting cellular apoptosis, but with significant association of type I collagen and α-SMA expression in HSC. [37] Comparable to the tumor environment expression levels of fibrosis related genes in HSCs were increased by overexpression of miR-200 family members (miR-200a, and 200b). [36] For example, miR-200a was decreased in TGF-β1-induced HSC activation and induced liver fibrosis.…”