Thrombomodulin Mitigates the Progression of Hepatocellular Carcinoma in Steatotic Liver

Introduction: Metabolic dysfunction associated steatotic liver disease promotes intrahepatic metastasis of liver cancer, although not uniformly. However, the mechanisms underlying steatosis-induced progression of liver cancer are not well understood. Antitumor properties of thrombomodulin (TM) are unknown. We aimed to investigate whether TM contributes to the suppression of hepatocellular carcinoma (HCC) progression in the steatotic livers of mice. Methods: Mice were fed a normal or choline-deficient diet (CDD) for 4 weeks, followed by splenic injection of mouse Hepa1-6 cells. Hepatic tumors were analyzed 3 weeks after the injection. Results: CDD induced hepatic steatosis, which resulted in a hypoxic state and the downregulation of TM in the liver. CDD-induced hepatic steatosis promoted HCC progression and increased serum levels of high motility group box 1 (HMGB-1), which were suppressed by recombinant TM (rTM). However, HCC progression was not promoted in non-steatotic livers. In TM +/- mice with hepatic steatosis, of which endogenous TM was severely down-regulated, ischemia-reperfusion significantly enhanced HCC progression compared to that in wild-type mice with steatotic livers, both of which were also ameliorated by rTM. In vitro, hypoxia promoted Hepa1-6 cell motility and secretion of HMGB-1 from the Hepa1-6 cells, and the addition of HMGB-1 also enhanced the motility of the Hepa1-6 cells in the non-hypoxic state, which was suppressed by rTM and anti-HMGB-1 antibodies. Discussion: These findings suggest that hepatic steatosis has a prometastatic effect through the downregulation of TM. TM has a tumor-suppressive function via the inhibition of HMGB-1 activity. Plain Language Summary: Steatotic liver reduces the expression of TM and accelerated the progression of HCC by decreasing the capacity of TM to absorb HMGB-1. rTM may be a useful modality to prevent HCC progression in steatotic livers during hepatic surgery.