Tumorigenesis of Hepatocellular Carcinoma Related to Metabolic Disorders With a Focus on the Hippo Pathway

The Hippo pathway has been implicated in the tumorigenesis of hepatocellular carcinoma (HCC). We aimed to determine the expression of Hippo pathway-related proteins in HCC using immunohistochemical staining and compare the data among patients with different underlying clinical background diseases. We collected 40 resected HCC formalin-fixed paraffin-embedded samples and categorized them into 4 groups according to pre-existing conditions [17 samples of alcohol consumption (HCC-A) and 6, 8, and 9 samples with hepatitis B virus infection (HCC-B), hepatitis C virus infection (HCC-C), and metabolic diseases (HCC-M), respectively]. Using immunohistochemistry, we investigated the Hippo pathway-related proteins YAP1, CADM1, and SOX9. Hypertension was the most common disease (72.5%) among patients with HCC, followed by diabetes mellitus (47.5%). Regarding the background liver disease, significant findings of steatohepatitis (SH) were observed in the HCC-A (35.3%) and HCC-M (88.9%) groups compared with those in the HCC-B (16.7%) and HCC-C (0%) groups. A significant finding of metabolic dysfunction-associated SH (MASH) was also observed in the HCC-M group (88.9%), and liver cirrhosis was predominantly observed in the HCC-C group (100%). Twenty-seven patients had Hippo-inactive status, and 13 patients had active status. SH was more predominant in the HCC-M group with Hippo inactivity (100%) than in the HCC-A group (50.0%). The average tumor size was significantly larger in the Hippo-inactive group than in the Hippo-active group. Hippo pathway-associated proteins could serve as potential therapeutic targets for MASH and MASH-related HCC if the Hippo pathway is inactivated.