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.
Highlights
Liver fibrosis is a chronic disease that a repairing procedure happens upon liver injury, resulting in excessive generation of extracellular matrix (ECM), mainly containing type I and III collagens, by the activated hepatic stellate cells (HSCs) [1]
Our study verified that long non-coding RNAs (lncRNAs) NEAT1 could target and decrease (Fig. 1G). These results reveal that NEAT1 upregulation suppress the expression of miR-139-5p directly to promote HSCs and miR-139-5p downregulation might be closely correlated with activation and excerabate liver fibrosis via β-catenin/SOX9/TGF-β1 liver fibrogenesis
Liver fibrosis is caused by almost all chronic liver diseases, resulting in the progress of cirrhosis and related complications [29]
Summary
Liver fibrosis is a chronic disease that a repairing procedure happens upon liver injury, resulting in excessive generation of extracellular matrix (ECM), mainly containing type I and III collagens, by the activated HSCs (aHSCs) [1]. Our study verified that lncRNA NEAT1 could target and decrease (Fig. 1G) These results reveal that NEAT1 upregulation suppress the expression of miR-139-5p directly to promote HSCs and miR-139-5p downregulation might be closely correlated with activation and excerabate liver fibrosis via β-catenin/SOX9/TGF-β1 liver fibrogenesis. The overexpression of TGF-β1 significantly promoted LX-2 cells proliferation and migration (Fig. 6H, I) These results demonstrates that miR-139-5p regulates HSCs activation depending on β-catenin/SOX9/TGF-β1 signaling pathway. The protein expression levels of profibrotic markers β-catenin, SOX9, TGF-β1, α-SMA, Collagen-I, and TIMP-1 in murine fibrotic liver tissues showed the same results (Fig. 8E, F). The mRNA and protein levels of profibrotic markers α-SMA, Collagen-I, and TIMP-1 in murine fibrotic liver tissues further validated above results (Fig. S1G-I) These results demonstrate that LncRNA NEAT1 exacerbated liver fibrosis by suppressing the expression of miR-139-5p. The downregulation of NEAT1 and overexpression of miR-139-5p suppress the expression of profibrotic markers in murine fibrosis models via targeting β-catenin/SOX9/TGF-β1 pathway (Fig. S2)
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