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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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC8446030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Retinoblastoma (RB) is the most common intraocular tumor in childhood. Long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NTAT1) has been reported to be related to RB progression. This study aims to study the molecular mechanism of NEAT1 in regulating cell cycle, proliferation, apoptosis, migration, and invasion in RB. The expression levels of NEAT1 and miR-3619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of LIM and SH3 domain protein 1 (LASP1) was measured by western blot. The proliferation of RB cells was analyzed by cell counting kit-8 (CCK-8) and cell colony formation assays. Cell migration and invasion were evaluated by transwell assay. Cell cycle and apoptosis were assessed by flow cytometry analysis. The association between miR-3619-5p and NEAT1 or LASP1 was predicted by starBase 3.0 database and identified by dual-luciferase reporter assay. The effects of NEAT1 knockdown on the tumor growth in vivo were detected by in vivo tumor formation assay. NEAT1 expression was dramatically up-regulated, and miR-3619-5p expression was obviously downregulated in RB tissues and cells compared with control groups. The protein level of LASP1 was obviously increased in RB tissues or cells relative to paracancerous normal tissues or cells, respectively. Functionally, NEAT1 silencing inhibited RB cell migration, invasion, and proliferation, whereas induced cell apoptosis and cell cycle arrest in RB; this phenomenon was partially abolished by miR-3619-5p inhibitor. Mechanistically, NEAT1 acted as a sponge of miR-3619-5p, and miR-3619-5p was associated with LASP1. In addition, NEAT1 knockdown decreased the volume and weight of RB tumor in vivo. Together, NEAT1 silencing repressed cell migration, invasion, and proliferation, whereas induced cell apoptosis and cycle arrest by sponging miR-3619-5p to inhibit LASP1 expression in RB cells. This study may provide a theoretical basis for RB therapy.

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

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