miR-301a-3p promotes hepatic stellate cells activation and liver fibrogenesis via regulating PTEN/PDGFR-β.

Abstract

Hepatic fibrosis is an essential pathology of multiple chronicliverdiseases. The aim of this study was to investigate the role of miR-301a-3p in hepatic fibrosis. We found that miR-301a-3p was upregulated in hepatic fibrosis patients and in culture-activated human hepatic stellate cells (HSCs). Interestingly, miR-301a-3p expression was increased in hepatic fibrosis progression mice while decreased in hepatic fibrosis recovery mice, indicating that miR-301a-3p may participate in the hepatic fibrosis pathology. Functionally, the effects of miR-301a-3p both on hepatic fibrosis progression and regression were assessed in vivo. Inhibiting miR-301a-3p amelioratedmouse liver fibrogenesis and collagen deposition and suppressed HSC activation and fibrogenic factor expression. Whereas, in hepatic fibrosis regression, upregulating miR-301a-3p impaired mouse hepatic fibrosis recovery by inducing HSC activation and triggering inflammation. Consistently, gain-of-function and loss-of-function analysis of miR-301a-3p were performed to evaluate its effects on human HSCs LX-2 cell. We found that suppressing miR-301a-3p inhibited LX-2 cell activation and proliferation, and induced LX-2 cell apoptosis, accompaniedby decreased fibrotic mediators expression. Collectively, these findings suggest miR-301a-3p drives liver fibrogenesis and HSC activation in hepatic fibrosis. Mechanistically, we demonstrated miR-301a-3p binds directly to phosphatase and tensin homolog (PTEN) by luciferase reporter analysis, pull-down, and RIP assay. Indicating that miR-301a-3p plays a critical rolein promotingliverfibrogenesis viamodulating the PTEN/platelet derived growth factor β (PDGFR-β) pathway. In conclusion, our findings demonstrate that miR-301a-3p expression is closely correlated with hepatic fibrosis pathology, and that enhancing miR-301a-3p maintains the HSC profibrogenic phenotype, triggers inflammatoryresponses, promotes fibrogenic factor production, and further exacerbates liver fibrogenesis. These findings suggest that miR-301a-3p may serve as a promising diagnostic and prognosis biomarker for hepatic fibrosis treatment.

• Authors: Xin Chen, Sai Zhu, Si-Yu Chen, Jia-Nan Wang, Li-Jiao Sun, Shan-Min Tao, Xiao-Feng Li, Hai-Di Li, Ying-Yin Sun, Chuan-Hui Xu, Xiao-Guo Suo, Ming-Lu Ji, Cheng Huang, Xiao-Ming Meng, Jun Li
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 110 Pg. 109034 (Sep 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35834952 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• MIRN301 microRNA, mouse
• MicroRNAs
• Proto-Oncogene Proteins c-sis
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Proliferation
• Hepatic Stellate Cells (pathology)
• Humans
• Liver Cirrhosis (metabolism)
• Mice
• MicroRNAs (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Proto-Oncogene Proteins c-sis (pharmacology)
• Signal Transduction