Abstract
BackgroundCircular RNAs (circRNAs) are considered as key regulators of cancer biology. Recently, cMTO1 (a circRNA derived from MTO1 gene, hsa_circ_0007874) has been demonstrated to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the roles of cMTO1 in liver fibrosis are largely unknown.MethodsExpressions and roles of cMTO1 were examined in vivo and in vitro during liver fibrosis. The interaction between microRNA-181b-5p (miR-181b-5p) and cMTO1 was analyzed by luciferase activity assays and pull down assays.ResultscMTO1 was shown to be reduced in the liver from patients with cirrhosis. In addition, cMTO1 was down-regulated in the mouse fibrotic livers as well as activated hepatic stellate cells (HSCs). Restoring of cMTO1 led to a reduction in HSC proliferation. Results of immunofluorescence analysis showed that cMTO1 suppressed the expressions of α-SMA and type I collagen. cMTO1 was found to be expressed in the cytoplasm of HSCs. Further studies confirmed that cMTO1 and miR-181b-5p were co-located in the cytoplasm. Interestingly, there was an interaction between cMTO1 and miR-181b-5p. Results of luciferase reporter assays and pull down assays confirmed that miR-181b-5p could bind to cMTO1. cMTO1-inhibited HSC activation was blocked down by miR-181b-5p or PTEN. Meanwhile, PTEN was a target of miR-181b-5p.ConclusioncMTO1 inhibits HSC activation, at least in part, through miR-181b-5p-mediated PTEN expression. Our results also suggest that cMTO1 may be a novel therapeutic target in liver fibrosis.
Highlights
Liver fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix components, especially collagens (Friedman, 2008)
A growing body of evidence suggests that miRNAs participate in the control of hepatic stellate cell (HSC) activation, which is an essential event in liver fibrosis (Kim et al, 2019)
To determine whether cMTO1 exerts an effect on liver fibrosis, the liver cMTO1 expression in patients with cirrhosis was firstly detected
Summary
Liver fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix components, especially collagens (Friedman, 2008). MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs molecules that regulate gene expression by mRNA degradation and/or translation repression (Croce and Calin, 2005). MiRNAs have been reported cMTO1 in Hepatic Stellate Cell to be deregulated in various human diseases and involved in many biological processes such as cell proliferation (Ma et al, 2018; Bruch et al, 2019). MiRNAs are vital HSC regulators as well as promising therapeutic targets in liver fibrosis. Emerging evidence has revealed that circRNAs could sponge miRNAs in many cancers by acting as competing endogenous RNAs and thereby lead to the derepression of miRNA targets (Deng et al, 2018; Yu et al, 2018). The roles of cMTO1 in liver fibrosis are largely unknown
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