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- Title
miR-200a controls hepatic stellate cell activation and fibrosis via SIRT1/Notch1 signal pathway.
- Authors
Yang, Jing-Jing; Tao, Hui; Liu, Li-Ping; Hu, Wei; Deng, Zi-Yu; Li, Jun
- Abstract
Objectives: miR-200a has been established as a key regulator of HSC activation processes in liver fibrosis. Epigenetic silencing of miR-200a contributing to SIRT1 over-expression has been discussed in breast cancer; however, whether miR-200a controls SIRT1 gene expression in hepatic fibrosis is still unknown. Methods and materials: We analyzed miR-200a regulation of SIRT1 expression in CCl-induced liver fibrosis and TGF-β1-mediated activation of HSC. miR-200a, SIRT1, α-SMA, Col1A1, Notch1 and NICD expression were estimated by Western blotting, qRT-PCR and Immunohistochemistry. HSCs were transfected with miR-200a mimic, miR-200a inhibitor and SIRT1-RNAi. Luciferase reporter assays further confirmed the interaction between miR-200a and the SIRT1 mRNA 3'-UTR. Cell proliferation ability was assessed by MTT and cell cycle. Results: We found that treatment activated HSC with miR-200a mimics, restored miR-200a expression and reduced SIRT1 levels. Conversely, treatment activated HSC with miR-200a inhibitors, decreased miR-200a expression and up-regulated SIRT1 levels. Restoration of miR-200a or the knockdown of SIRT1 prevented HSC activation and proliferation. We have established the SIRT1 transcript as subject to regulation by miR-200a, through miR-200a targeting of SIRT1 3'-UTR. Finally, HSC transfected with SIRT1-siRNA increased the levels of Notch1 protein and mRNA expression. Conclusions: Our study demonstrated that miR-200a regulates SIRT1/Notch1 expression during HSC activation and fibrosis.
- Subjects
LIVER disease diagnosis; LIVER disease treatment; MICRORNA genetics; LUCIFERASE genetics; CELL proliferation
- Publication
Inflammation Research, 2017, Vol 66, Issue 4, p341
- ISSN
1023-3830
- Publication type
Article
- DOI
10.1007/s00011-016-1020-4