miR-511-3p promotes hepatic sinusoidal obstruction syndrome by activating Hedgehog pathway via targeting Ptch1.

BACKGROUND: As a major complication of hematopoietic stem cell transplantation, the incidence of hepatic sinusoidal obstruction syndrome (HSOS) is as high as 70%. Previous evidence has demonstrated that miR-511-3p was involved in HSOS, but the mechanism remains unclear. This study aims to examine the mechanism underlying miR-511-3p regulating HSOS.

METHODS: Monocrotaline (MCT) was used to create an HSOS rat model and to treat liver sinusoidal endothelial cells (LSECs). H&E and Masson staining were used to detect pathological changes in liver tissue. The expression of miR-511-3p and Hedgehog pathway-related proteins were assessed by qRT-PCR and Western blotting. The effect of miR-511-3p in regulating HSOS was investigated by MTT, ELISA assay and flow cytometry. Finally, the interaction between miR-511-3p and Ptch1 was determined by luciferase reporter assay.

RESULTS: The rats showed a typical HSOS phenotype, including LSEC damage, liver injury and fibrosis after MCT administration. miR-511-3p was upregulated in hepatic tissue of rat HSOS model and MCT-induced LSECs. miR-511-3p directly targeted patched1 (Ptch1) and suppressed Ptch1 expression while activated the Hedgehog signaling pathway. Depletion of miR-511-3p showed a protective effect against MCT-induced HSOS, as evidenced by decreased HSOS pathogenesis factors, MMP-2, MMP-9, TNF-α and IL-1β, and decreased LSEC apoptosis rates. Nevertheless, knockdown of Ptch1 reversed the protective effect of miR-511-3p depletion against MCT-induced LSEC injury and apoptosis.

CONCLUSIONS: miR-511-3p aggravates HSOS by activating the Hedgehog signaling pathway through targeting Ptch1, and miR-511-3p may develop as the potential therapy for the treatment of HSOS.