hsa_circ_0004018 suppresses the progression of liver fibrosis through regulating the hsa-miR-660-3p/TEP1 axis

Abstract

Efforts have been made in the prevention and treatment of liver fibrosis. The inhibition or depletion of the hepatic stellate cells (HSCs) has been considered as a potential approach. Recently, there are numbers of studies about the role of the circular RNA in the disease progression. However, the role of circular RNA in the regulation of HSCs and the progression of liver fibrosis remained elusive. In this study, we constructed a CCl4-induced liver fibrosis mouse model and overexpressed hsa_circ_0004018 in HSCs. Then, salvianolic acid B was used to treat HSCs in vitro. We found that hsa_circ_0004018 is downregulated in liver fibrogenesis. Luciferase reporter assay was performed to verify the interaction of hsa_circ_0004018, hsa-miR-660-3p and TEP1. It showed that hsa_circ_0004018 may act as a sponge of hsa-miR-660-3p, which can target and downregulate the expression of TEP1. hsa_circ_0004018 expressing lentivirus was used to investigate the in-vivo function of hsa_circ_0004018 in CCl4-induced liver fibrosis mice. We also reveal that the hsa_circ_0004018/hsa-miR-660-3p/TEP1 axis contributes to the proliferation and activation of HSCs. In addition, the overexpression of hsa_circ_0004018 alleviated the progression of liver fibrosis. In conclusion, our study highlights hsa_circ_0004018 as a potential biomarker and therapeutic target for liver fibrosis.

Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis

“…Currently, more and more circRNAs are identified to act as crucial regulators in multiple pathological and physiological processes of many types of disease. Previous studies have showed that circRNAs can regulate the activation and proliferation of HSCs by usually acting as miRNA sponges, thus to involve in the process of liver fibrosis in liver failure (Ji et al., 2020 ; Li et al., 2020 ). In this study, we first investigated that circDIDO1 overexpression could suppress the proliferation, reduced pro-fibrotic markers α-SMA and collagen I, and induced apoptosis as well as cell cycle arrest in HSCs, thus repressing HSC activation.…”

Noncoding RNAs Interactions in Hepatic Stellate Cells during Hepatic Fibrosis

“…FBXW7 also prevented the ZFP36-mediated autophagy inactivation in isolated murine HSC by acting as a decoy to ZFP36, thus sensitizing the HSCs to a ferroptosis (a program of cell death) [172]. The last reported circRNA is the circ_0004018 that was reduced in the activated primary mouse HSCs [159]. In this study [159], circ_0004018 acts as a miR-660-3p sponge and causes the increase of Telomerase associated protein 1 (Tep1) expression.…”

“…The last reported circRNA is the circ_0004018 that was reduced in the activated primary mouse HSCs [159]. In this study [159], circ_0004018 acts as a miR-660-3p sponge and causes the increase of Telomerase associated protein 1 (Tep1) expression. Although the function of Tep1 in HSC activation is unknown, the increase of both circ_0004018 and Tep1 suppress HSC proliferation [159].…”

Circular RNA as An Epigenetic Regulator in Chronic Liver Diseases

“…Telomeraseassociated protein 1 (TEP1), a component of telomerase and target of hsa-miR-660-3p [102], plays a key role in the development of liver fibrosis and cirrhosis [103]. Overexpression of hsa_circ_0004018, a sponge of hsa-miR-660-3p, increases the expression of TEP1 and significantly suppresses the proliferation and activation of HSCs [104]. Consistently, hsa_circ_0007874 (cMTO1) could inhibit HSC activation through sponging miR-181b-5p and miR-17-5p [105,106].…”