STE20-Type Kinases MST3 and MST4 Act Non-Redundantly to Promote the Progression of Hepatocellular Carcinoma

Abstract

Abstract Aims Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing malignancies. Recently, non-alcoholic steatohepatitis (NASH), characterized by liver steatosis, inflammation, cell injury (hepatocyte ballooning), and different stages of fibrosis, has emerged as a major catalyst for HCC. Because the STE20-type kinases MST3 and MST4 have been described as critical molecular regulators of NASH pathophysiology, we here focused on determining the relevance of these proteins in human HCC. Methods The clinical importance of MST3 and MST4 in HCC was assessed in publicly available datasets and by qRT-PCR analysis of a validation cohort recruited at the University Hospital of Tübingen (n = 48 for HCC patients and n = 214 for control subjects). The functional significance of MST3 and MST4 was examined in HepG2 and Hep3B cells transfected with MST3, MST4, or MST3/4 small interfering RNA. Potential downstream pathways were investigated by co-immunoprecipitation and Western blotting. Results By analyzing public datasets and in-house cohorts, we found that hepatic MST3 and MST4 expression was positively correlated with the incidence and severity of HCC. We also found that the silencing of both MST3 and MST4, but also either of them individually, markedly suppressed the tumorigenesis of human HCC cells including attenuated proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistic investigations revealed lower activation of STAT3 signaling in MST3/MST4-deficient hepatocytes, and identified GOLGA2 and STRIPAK complex as the binding partners of both MST3 and MST4 in HCC cells. Conclusions These findings reveal that MST3 and MST4 play a critical role in promoting the progression of HCC and suggest that targeting these kinases may provide a novel strategy for the treatment of liver cancer.