Peking University, China
Title: Down-regulation of miR-185 in liver fibrosis correlates with RHEB and RICTOR overexpression and HSCs activation
Activation of hepatic stellate cells (HSCs) into collagen producing myofibroblasts is critical for pathogenesis of liver fibrosis. Recent studies have shown effect of microRNAs (miRNAs) on regulating HSC activation during liver fibrosis. Here, we aimed to explore the roles of miR-185 in human liver fibrosis. Expression of plasma miR-185 was detected in HBV-related liver fibrosis patients (S2/3, n=10) and the liver cirrhosis patients (n=8) by quantitative real time polymerase chain reaction (qRT-PCR), and healthy volunteers was selected (n=8) as control group. We found that the expression of plasma miR-185 in the HBV-related liver fibrosis patients was significantly downregulated. Carbon tetrachloride (CCl4)-induced mice fibrotic liver tissues and TGF-β1-induced activated HSCs also present down-regulation of miR-185 concomitant with increased expression of RHEB and RICTOR. To analyze the correlation of RHEB and RICTOR expression with miR-185, LX2 cells were transiently transfected with miR-185 mimics, and the expression of α-SMA, collagen â… and collagen â…¢ was decreased as well as the expression of RHEB and RICTOR. Furthermore, dual-luciferase reporter assays indicated that miR-185 inhibited the expression of RHEB and RICTOR through direct targeting their 3’UTR regions. Moreover, knockdown of RHEB and RICTOR suppressed α-SMA and collagenâ… and collagen â…¢ in HSCs. In conclusion, miR-185 prevents liver fibrogenesis by inhibiting HSC activation through inhibiting RHEB and RICTOR. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-185.