Salvianolic acid B exerts an anti-hepatocellular carcinoma effect by regulating the Hippo/YAP pathway and promoting pSmad3L to pSmad3C simultaneously

Abstract

Salvianolic acid B (Sal B) is a component obtained from Salvia miltiorrhiza and is empirically used for liver diseases. The TGF-β/Smad and Hippo/YAP pathways may interact with each other in hepatocellular carcinoma (HCC). Previously, we found that Sal B mediates the TGF-β/Smad pathway in mice and delays liver fibrosis-carcinoma progression by promoting the conversion of pSmad3L to pSmad3C, but the effect of Sal B on the Hippo/YAP pathway has not been determined. Therefore, we used a DEN/CCl4/C2H5OH-induced liver cancer model in mice to analyze liver index and tumor incidence, detect AST and ALT serological markers, observe liver pathology and the number of Ki67-positive cells to evaluate the anti-HCC effect of Sal B in vivo. We used a TGF-β1-induced HepG2 cell model, and applied an MST1/2 inhibitor, XMU-MP-1, to detect the changes in pSmad3C/pSmad3L signaling induced by MST1/2 inhibition. Sal B significantly inhibited tumorigenesis in DEN/CCl4/C2H5OH-induced mice in vivo, and suppressed the growth of HepG2 cells by inhibiting cell proliferation and migration in vitro. Here, our study also validated the role of Sal B in reversing XMU-MP-1-induced proliferation and migration of HepG2 cells in vitro. Most importantly, we elucidated for the first time the potential mechanism of Sal B against HCC via the Hippo/YAP pathway, which may be specifically related to upregulation of MST1 and inhibition of its downstream effector protein YAP. In conclusion, these findings indicate that Sal B possesses anti- HCC effects both in vivo and in vitro by regulating the Hippo/YAP pathway and promoting pSmad3L to pSmad3C synchronously.