Abstract
Effective control of hepatic stellate cell (HSC) activation and proliferation is critical to the treatment of liver fibrosis. Long non-coding RNAs have been shown to play a pivotal role in the regulation of cellular processes. It has been reported that growth arrest-specific transcript 5 (GAS5) acts as a crucial mediator in the control of cell proliferation and growth. However, little is known about the role and underlying mechanism of GAS5 in liver fibrosis. In this study, our results indicated that GAS5 expression was reduced in mouse, rat, and human fibrotic liver samples and in activated HSCs. Overexpression of GAS5 suppressed the activation of primary HSCs in vitro and alleviated the accumulation of collagen in fibrotic liver tissues in vivo. We identified GAS5 as a target of microRNA-222 (miR-222) and showed that miR-222 could inhibit the expression of GAS5. Interestingly, GAS5 could also repress miR-222 expression. A pulldown assay further validated that GAS5 could directly bind to miR-222. As a competing endogenous RNAs, GAS5 had no effect on primary miR-222 expression. In addition, GAS5 was mainly localized in the cytoplasm. Quantitative RT-PCR further demonstrated that the copy numbers of GAS5 per cell are higher than those of miR-222. GAS5 increased the level of p27 protein by functioning as a competing endogenous RNA for miR-222, thereby inhibiting the activation and proliferation of HSCs. Taken together, a new regulatory circuitry in liver fibrosis has been identified in which RNAs cross-talk by competing for shared microRNAs. Our findings may provide a new therapeutic strategy for liver fibrosis.
Highlights
Long non-coding RNAs function as competing endogenous RNAs
growth arrest-specific transcript 5 (GAS5) Is Down-regulated in Liver Fibrosis and in Activated hepatic stellate cell (HSC)—To determine whether GAS5 expression is altered during liver fibrosis, the degree of liver fibrosis was evaluated by staining with Sirius Red (Fig. 1A). quantitative real time PCR (qRT-PCR) results demonstrated that the levels of collagen 1a1 (Col1A1) and ␣-SMA in CCl4 mice were increased compared with those in control mice (Fig. 1F)
The reduction of GAS5 during fibrosis progression was observed in another mouse liver fibrosis model of bile duct ligation (Fig. 1, B and H)
Summary
Whether growth arrest-specific transcript 5 (GAS5) acts as a ceRNA for microRNA-222 in liver fibrosis remains undefined. Results: GAS5 increases p27 expression as a ceRNA for microRNA-222, thereby inhibiting liver fibrosis progression. Effective control of hepatic stellate cell (HSC) activation and proliferation is critical to the treatment of liver fibrosis. GAS5 increased the level of p27 protein by functioning as a competing endogenous RNA for miR-222,. We showed that the expression of GAS5 is down-regulated in fibrotic liver tissues and in activated HSCs. Importantly, overexpression of GAS5 alleviated the activation of primary HSCs in vitro and reduced the accumulation of collagen in vivo. We discovered that GAS5 increases the level of p27 protein by functioning as a ceRNA for miR-222, thereby inhibiting the activation and proliferation of HSCs
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