Long Non-coding RNA Growth Arrest-specific 5 Inhibits Liver Fibrogenesis in Biliary Atresia by Interacting with MicroRNA-222 and Repressing IGF1/AKT Signaling

Overview

Journal Transl Pediatr

Publisher AME Publishing Company

Specialty Pediatrics

Date 2024 Jan 10

PMID 38197105

Authors

Ruoyi Wang

Ya Gao

Affiliations

Soon will be listed here.

Abstract

Background: Long non-coding RNA growth arrest-specific 5 (lncRNA GAS5) has been shown to inhibit liver fibrosis through serving as a competing endogenous RNA for microRNA-222 (miR-222). Progressive liver fibrosis is a typical characteristic of biliary atresia (BA). However, the role of GAS5/miR-222 and its underlying mechanisms remain largely unknown in BA.

Methods: The expression of GAS5 was determined in the liver and primary hepatic stellate cells (HSCs) of BA patients. Then, the effects of GAS5 on the activation and proliferation of HSCs were evaluated. Furthermore, the interaction between GAS5 and miR-222 was investigated by a luciferase gene report assay. Next, the effects of IGF1/AKT signaling were determined to clarify the downstream mechanism of GAS5. Finally, GAS5 administration was performed to explore its role in an experimental BA mouse model.

Results: GAS5 expression was decreased in liver tissues and HSCs of BA patients, and was inversely correlated with liver fibrosis in BA. Up-regulation of GAS5 in LX-2 cells significantly reduced smooth muscle α-actin (α-SMA) and collagen 1a1 (COL1A1) expression, inhibited cell proliferation and clone formation ability, induced S phase increase, and promoted cell apoptosis. Moreover, GAS5 was negatively regulated by miR-222, which promoted HSCs activation and proliferation, and was positively correlated with liver fibrosis in BA. Additionally, the expressions of IGF1, p-PI3K, and p-AKT were decreased when LX-2 cells over-expressed GAS5, whereas knockdown of IGF1 or AKT significantly decreased α-SMA and COL1A1 expression, suppressed cell proliferation, and enhanced cell apoptosis in LX-2 cells. Furthermore, GAS5 administration significantly increased apoptosis and reduced liver fibrosis, α-SMA and COL1A1 expressions in liver tissues of BA mice.

Conclusions: GAS5 inhibited liver fibrosis in BA by interacting with miR-222 and regulating IGF1/AKT signaling, which may be a therapeutic target to alleviate liver fibrosis in BA.

Citing Articles

Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis.

Wade H, Pan K, Zhang B, Zheng W, Su Q eGastroenterology. 2025; 2(4):e100115.

PMID: 39872125 PMC: 11729351. DOI: 10.1136/egastro-2024-100115.

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