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

Abstract

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 (Mst1/2ΔHep) mice. Mst1/2ΔHep 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&Hmgb1ΔHep 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&Hmgb1ΔHep mice were smaller, developed hyperbilirubinemia, had more liver injury with intrahepatic biliary defects, and had reduced hemoglobin compared to Mst1/2ΔHep mice. Conclusion: Hepatic HMGB1 promotes hepatocarcinogenesis by regulation of YAP activity; nevertheless, it maintains intrahepatic bile duct physiology under Hippo signaling deficiency.

Overexpression of HMGB1 in hepatocytes accelerates PTEN inactivation-induced liver cancer

“…Our study showed that ablation of Hmgb1 reduced the number of F4/80 + cells in Mst1/2 -deficient livers and was associated with reduced HCC proliferation. 26 Here, we observed increased number of F4/80 + cells, at 9 months, and increased F4/80 staining, at 3 months, in Hmgb1 compared to empty AAV8-injected mice. Although not significant, the overall number of F4/80 + cells was increased in Hmgb1 compared to empty AAV8-injected female Pten ∆Hep mice (Figure 6 C, Supplemental Figure S11C–E, http://links.lww.com/HC9/A656 ).…”

“…We reported that HMGB1 expression is higher in primary liver cancer compared to healthy control in the human The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort. 26 Further analysis of RNA-seq data set GSE107943 from patients with iCCA showed increased expression of HMGB1 in tumor versus nontumor, irrespective of MASH (Figure 1 C). Overall, these observations indicate that HMGB1 transcripts increase in patients with MASH and liver cancer.…”

“…We showed that ablation of Hmgb1 in Hippo pathway-deficient mice, reduces yes-associated protein (YAP) activity. 26 To examine if overexpression of HMGB1 supports nuclear YAP localization and activity, thus inducing liver cancer in Pten ∆Hep mice, we performed YAP immunohistochemistry. In nontumor tissues from empty and Hmgb1 AAV8-injected Pten ∆Hep mice, YAP staining was cytoplasmic in hepatocytes but nuclear in biliary epithelial cells.…”

“…We proved that HMGB1 regulates YAP activity and hepatocarcinogenesis in Hippo signaling-deficient mice. 26 Deletion of Pten induces liver cancer my means of the Hippo/YAP/TAZ pathway, where deficiency of Pten and Hippo signaling accelerates metabolic dysfunction-associated steatotic liver disease and liver cancer. 35 Another study showed that Pten -deleted SOX9 + cells give rise to mixed HCC-iCCA tumors.…”

Advanced Biomarkers of Hepatotoxicity in Psychiatry: A Narrative Review and Recommendations for New Psychoactive Substances

“…HMGB1 acts as an anti-tumour protein, regulating the immune cell response during the process of carcinogenesis, with the implication that abnormal HMGB1 expression is associated with the oncogenesis, development and metastasis of cancer [88]. According to Athavale et al, ablation of HMGB1 in the liver reduces hepatocellular carcinoma but causes hyperbilirubinaemia in mice deficient in Hippo signalling [89]. Other studies indicate that HMGB1 may be an important marker for assessing tumour staging and predicting prognosis in hepatocellular carcinoma, as HMGB1 levels in hepatocellular carcinoma were significantly higher than in chronic hepatitis, cirrhosis and healthy controls.…”