Inhibition of MST1/2 attenuates the anti-hepatocarcinogenesis effect of Salvianolic acid B via the ERK/MAPK signaling pathway.

Abstract

<p>Salvianolic acid B (Sal B), extracted from Salvia miltiorrhiza, has a commendable effect on liver-related disease. The Hippo/YAP and MAPK pathways were reported to exert synergistic effect on hepatocarcinogenesis. Our group has demonstrated that Sal B could restrain the MAPK pathway and postpone the hepatic fibrosis process. Also, Sal B exhibits anti-tumor activity by regulating the Hippo/YAP signaling. Simultaneously, the inhibition of the MAPK pathway could diminish the YAP expression in HepG2 cells; thus, we investigated the impact of MST1/2 gene double knockout (DKO) on the MAPK signaling pathway during hepatocarcinogenesis. Furthermore, the role of ERK/MAPK pathway in the interference of Hippo/YAP signaling associated with the anti-hepatocarcinogenic actions of Sal B was explored. DEN/CCl4/C2H5OH-induced liver fibrosis and cancer in MST1/2 DKO mice and TGF-β1/XMU-MP-1 (MST1/2 inhibitor)-stimulated or YAP-shRNAs/pEGFP lentiviral transfected hepatic stellate cells or hepatoma cells were employed in this study. In vivo, our results demonstrated that MST1/2 DKO attenuated Sal B's curative histopathological and serological outcomes, and its mechanism of action involves the activation of the MAPK signaling pathway, notably the ERK/MAPK. In vitro, studies showed that MST1/2 inhibitor promoted the activation of MAPK pathway resulting in weakened the inhibitory effect of Sal B. Meanwhile, reduced YAP boosted Sal B's suppressive roles on proliferation, migration, and apoptosis accompanied by suppression of pERK and pJNK, and activation of pp38. The ERK1/2 inhibitor further validated the role of YAP/TAZ in the moderating effect of Sal B's anti-carcinogenesis. This study revealed MST1/2 as a pivotal target for Sal B through which it prevents hepatocarcinogenesis via the ERK/MAPK signaling pathway.</p>