Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic PathwaysSummary

• Published in: Cellular and molecular gastroenterology and hepatology 2022-01, Vol.13 (2), p.405-423
• Main Authors: Yeshwant Kurhe, Mara Caputo, Emmelie Cansby, Ying Xia, Sima Kumari, Sumit Kumar Anand, Brian W. Howell, Hanns-Ulrich Marschall, Margit Mahlapuu
• Format: Article
• Language: English
• Subjects: CDAA; DEN; Hepatocellular Carcinoma; NASH; STK25
• ISSN: 2352-345X; 2352-345X

Background & Aims: Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, nonalcoholic 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, to advance the prevention and treatment of NASH-driven HCC. Because the sterile 20-type kinase serine/threonine kinase 25 (STK25) exacerbates NASH-related phenotypes, we investigated its role in HCC development and aggravation in this study. 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 was combined with a high-fat diet-feeding. In the second cohort, chronic administration of carbon tetrachloride was combined with a choline-deficient L-amino-acid–defined 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 showed a 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 decreased compensatory proliferation, by a mechanism that involves 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 evidence that antagonizing 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 human beings.