BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, non-alcoholic steatohepatitis (NASH) has been recognized as a major catalyst for HCC. Thus, additional research is critically needed to identify mechanisms involved in NASH-induced hepatocarcinogenesis, in order to advance the prevention and treatment of NASH-driven HCC. Since the STE20-type kinase STK25 exacerbates NASH-related phenotypes, here we investigated its role in HCC development and aggravation.
METHODS: Hepatocarcinogenesis was induced in the context of NASH in Stk25 knockout and wild-type mice by combining chemical procarcinogens and a dietary challenge. In the first cohort, a single injection of diethylnitrosamine (DEN) was combined with a high-fat diet feeding. In the second cohort, a chronic administration of carbon tetrachloride was combined with a choline-deficient L-amino-acid-defined (CDAA) diet. To study the cell-autonomous mode-of-action of STK25, we silenced this target in the human hepatocarcinoma cell line HepG2 by small interfering RNA.
RESULTS: In both mouse models of NASH-driven HCC, the livers from Stk25-/- mice displayed markedly lower tumor burden compared with wild-type controls. We also found that genetic depletion of STK25 in mice suppressed liver tumor growth through reduced hepatocellular apoptosis and lowered compensatory proliferation, by a mechanism that involves the protection against hepatic lipotoxicity and inactivation of STAT3, ERK1/2, and p38 signaling. Consistently, silencing of STK25 suppressed proliferation, apoptosis, migration, and invasion in HepG2 cells, which was accompanied by lower expression of the markers of epithelial-mesenchymal transition and autophagic flux.
CONCLUSIONS: This study provides the first evidence that antagonizing of STK25 signaling hinders the development of NASH-related HCC and provides an impetus for further analysis of STK25 as a therapeutic target for NASH-induced HCC treatment in humans.