Ablation of high‐mobility group box‐1 in the liver reduces hepatocellular carcinoma but causes hyperbilirubinemia in Hippo signaling‐deficient mice

Silencing the Hippo kinases mammalian sterile 20‐like 1 and 2 (MST1/2) activates the transcriptional coactivator yes‐associated protein (YAP) in human hepatocellular carcinoma (HCC). Hepatocyte‐derived high‐mobility group box‐1 (HMGB1) regulates YAP expression; however, its contribution to HCC in the context of deregulated Hippo signaling is unknown. Here, we hypothesized that HMGB1 is required for hepatocarcinogenesis by activating YAP in Hippo signaling‐deficient (Mst1/2 (ΔHep)) mice. Mst1/2 (ΔHep) mice developed HCC within 3.5 months of age and had increased hepatic expression of HMGB1 and elevated YAP activity compared to controls. To understand the contribution of HMGB1, we generated Mst1/2&Hmgb1 (ΔHep) mice. They exhibited decreased YAP activity, cell proliferation, inflammation, fibrosis, atypical ductal cell expansion, and HCC burden at 3.5 months compared to Mst1/2 (∆Hep) mice. However, Mst1/2&Hmgb1 (ΔHep) mice were smaller, developed hyperbilirubinemia, had more liver injury with intrahepatic biliary defects, and had reduced hemoglobin compared to Mst1/2 (ΔHep) mice. Conclusion: Hepatic HMGB1 promotes hepatocarcinogenesis by regulation of YAP activity; nevertheless, it maintains intrahepatic bile duct physiology under Hippo signaling deficiency.