Salvianolic Acid B Targets Mortalin and Inhibits the Migration and Invasion of Hepatocellular Carcinoma via RECK/STAT3 Pathway

Abstract

1) Background: Tumor migration and invasion is a complex and diverse process, including epi-thelial-mesenchymal transition (EMT) of tumor cells, and degradation of extracellular matrix by matrix metalloproteases (MMPs). Mortalin is an important oncogene. It has been reported that it plays an important role in tumor migration and invasion through various signaling pathways; however, the underlying mechanism still needs to be further explored. 2) Methods: At present, we studied the role of mortalin in the migration of HCC cell lines HepG2 and HCCLM3 cells. 3) Results: Our results showed that overexpression of Mortalin in HepG2 cells, decreases the protein level of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), activates the phos-phorylation and acetylation of STAT3, thereby upregulates matrix metalloproteinase 9 (MMP9) and promotes the cell migration and invasion. On the contrary, in HCCLM3 cells, mortalin knockdown increases the expression of RECK, inhibits the STAT3 pathway and the activity of MMP9, and promotes the cell migration and invasion. Furthermore, we found that Salvianolic acid B, a caffeic acid phenethyl ester analogue, specific binds to mortalin, and increases the degradation of mortalin proteasome through ubiquitination, thereby up-regulating RECK, inhibiting STAT3 and finally inhibiting the migration and invasion of HCC. 4) Conclusion: Our work suggests that mortalin is a potential therapeutic target for hepatocellular carcinoma.