miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway

Abstract

Liver fibrosis is a patho-physiological process which can develop into cirrhosis, and hepatic carcinoma without intervention. Our study extensively investigated the mechanisms of lncRNA NEAT1 and miR-139-5p in regulating liver fibrosis progression. Our results demonstrated that the expression of lncRNA NEAT1 was increased and the expression of miR-139-5p was decreased in fibrotic liver tissues. LncRNA NEAT1 could sponge miR-139-5p and promoted hepatic stellate cells (HSCs) activation by directly inhibiting the expression of miR-139-5p. The co-localization of lncRNA NEAT1 with miR-139-5p was shown in the cytosols of activated HSCs. miR-139-5p upregulation could suppress the expression of β-catenin. The overexpression of β-catenin promoted HSCs activation. Moreover, we found that β-catenin could interact with SOX9 promoted HSCs activation. Our further studies demonstrated that SOX9 could bind with the TGF-β1 promoter and promoted the transcription activity of TGF-β1. The upregulation of TGF-β1 further promoted HSCs activation. In vivo study also suggested that lncRNA NEAT1 knockdown and miR-139-5p overexpression alleviated murine liver fibrosis. LncRNA NEAT1 exacerbated liver fibrosis by suppressing the expression of miR-139-5p. Collectively, our study suggested that miR-139-5p sponged by lncRNA NEAT1 regulated liver fibrosis via targeting β-catenin/SOX9/TGF-β1 Pathway.

Mechanism of action of non-coding RNAs and traditional Chinese medicine in myocardial fibrosis: Focus on the TGF-β/Smad signaling pathway

“…Such phenomenon was counteracted by TGF-β3, suggesting that Vgll3, a member of lncRNA, could promote the progression of cardiac fibrosis by activating the TGF-β3-related pathways ( Stawowy et al, 2004 ). Being different from the above studies, lncRNA nuclear enriched abundant transcript 1 (NEAT1) is closely associated with the progression of lung, liver, and kidney fibrosis ( Wang et al, 2019a ; Wang et al, 2021b ; Zhao et al, 2022 ). As reported, NEAT1 was significantly expressed in both HF patients and TAC-induced HF mouse models, inhibition of its expression attenuated the TGF-β1-induced cardiac fibrosis, GSK126 (an EZH2 inhibitor) weakened TGF-β1-induced downregulation of Smad7 expression and upregulation of p-Smad2/3, and upregulation of Smad7 reversed the cardiac fibrosis caused by NEAT1 over-expression ( Zhang et al, 2020b ).…”

From Phenomenon to Essence: A Newly Involved lncRNA Kcnq1ot1 Protective Mechanism of Bone Marrow Mesenchymal Stromal Cells in Liver Cirrhosis

“…[ 23 ] LncRNA NEAT1 was also upregulated in liver fibrosis and activated HSCs via sponging of miR‐139‐5p. [ 24 ] Our previous study found that Kcnq1ot1 is highly expressed in liver cirrhosis. [ 16 ] The present study showed that BMSCs treatment can downregulate Kcnq1ot1 expression in cirrhotic mouse models both in vivo and in vitro.…”

Role of noncoding RNAs in liver fibrosis

“…Different forms of ncRNAs may work together to have a synergistic effect in the pathogenesis and progression of liver fibrosis. For example, lncRNA nuclear enriched abundant transcript1 (lncRNA NEAT1) and miR-139-5p have a synergistic effect that exacerbates the development of liver fibrosis[ 30 ]. Another study has revealed that lncRNA metastasis-associated lung adenocarcinoma transcript1 (lncRNA MALAT1) upregulates expression of β-catenin and promotes liver fibrosis through the Wnt/β-catenin pathway[ 31 ].…”