Hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3

Abstract

Previous circular RNA (circRNA) microarray analyses have uncovered an abnormal expression of hsa_circ_0070963 in hepatic stellate cells (HSCs). However, the specific role of hsa_circ_0070963 in liver fibrosis remains unknown. Here, we show that hsa_circ_0070963 inhibits liver fibrosis via regulation of miR-223-3p and LEMD3. Moreover, we demonstrated that hsa_circ_0070963 levels were reduced during liver fibrosis while restoring hsa_circ_0070963 levels abolished HSC activation, with a reduction in α-SMA and type I collagen levels both in vitro and in vivo. Furthermore, hsa_circ_0070963 overexpression suppressed both cell proliferation and the cell cycle of HSCs. MiR-223-3p was confirmed as a target of hsa_circ_0070963 and was shown to be involved in the effects of hsa_circ_0070963 on HSC activation. Furthermore, LEMD3 was confirmed as a target of miR-223-3p and was shown to be responsible for the activation of HSCs. The interactions between hsa_circ_0070963, miR-223-3p, and LEMD3 were validated via bioinformatic analysis, luciferase reporter assays, and rescue experiments. Collectively, hsa_circ_0070963 appeared to function as a miR-223-3p sponge that inhibited HSC activation in liver fibrosis via regulation of miR-223-3p and LEMD3. Therefore, hsa_circ_0070963 may serve as a potential 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.…”

“…Recently, mounting evidence shows the effect of circRNAs on HSC activation, which is essential for the pathogenesis of liver fibrosis. For example, hsa_circ_0070963 overexpression suppressed HSC activation with the reductions of collagen I and α-SMA by sponging miR-223-3p (Ji et al., 2020 ). Wang et al.…”

Genome-wide identification and characterization of circular RNA in resected hepatocellular carcinoma and background liver tissue

“…Zhou et al showed that expression profiles for hepatic circRNAs were significantly different between chronic hepatitis B (CHB) and normal hepatic tissues, with 99 dysregulated circRNAs identified in total 29 . Ji et al, reported the involvement of circ_0070963 in liver fibrosis 30 . Unexpectedly, this study did not reveal any significant association between circRNA expression and HBV, HCV, or cirrhosis status.…”

Circular RNA as An Epigenetic Regulator in Chronic Liver Diseases

“…Consistently, hsa_circ_0007874 (cMTO1) could inhibit HSC activation through sponging miR-181b-5p and miR-17-5p [105,106]. Besides, hsa_circ_0070963 inhibits liver fibrosis via the regulation of miR-223-3p, which is related to HSC activation [107]. By targeting miR-18b-3p, circFBXW4 attenuates murine liver fibrogenesis with an anti-inflammation effect via inhibiting the activation and proliferation of HSCs, and inducing HSC apoptosis [108].…”