microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway

Abstract

microRNA-29b (miR-29b) is known to be associated with TGF-β-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of α-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3′UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed α-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b.

Downregulation of TRIM27 expression inhibits the proliferation of ovarian cancer cells in vitro and in vivo

“…26,27 AKT activation could enhance resistance to apoptosis and induce cell survival signaling through multiple downstream pathways. [28][29][30][31] Combined with these results, we speculate that TRIM27 knockdown could promote the activation of the p38MAPK pathway and suppress the activation of the PI3K/AKT pathway and then inhibit cell proliferation and induce cell apoptosis and cell cycle arrest. However, the exact effect mechanism of TRIM27 in ovarian carcinogenesis needs to be explored in the future.…”

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

“…[1][2][3] With the development of liver damage, the risk of cirrhosis and hepatocellular carcinoma (HCC) is increased. Generally, liver fibrosis is considered as a reversible disease and could be prevented from becoming advanced fibrotic process by effective treatments.…”

“…[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. 10 Other ncRNAs, such as long intergenic non-coding RNAs (lincRNAs) and the heterogeneous group of long non-coding RNAs (lncRNAs), have also been reported to be involved in human diseases.…”

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

“…Aetiological treatment, fpr example, antiviral treatment for chronic hepatitis B and C, can slow or halt liver fibrosis progression 27. MiRNA‐mediated silencing of target gene expression has been shown to prevent and reverse liver fibrosis 28. The goal of the present study was to analyse the potential anti‐fibrotic effect of miR‐30a.…”