Gankyrin drives malignant transformation of chronic liver damage-mediated fibrosis via the Rac1/JNK pathway

Hepatocarcinogenesis is a complex process involving chronic liver injury, inflammation, unregulated wound healing, subsequent fibrosis and carcinogenesis. To decipher the molecular mechanism underlying transition from chronic liver injury to dysplasia, we investigated the oncogenic role of gankyrin (PSMD10 or p28(GANK)) during malignant transformation in a transgenic mouse model. Here, we find that gankyrin increased in patients with cirrhosis. In addition to more severe liver fibrosis and tumorigenesis after DEN plus CCl(4) treatment, hepatocyte-specific gankyrin-overexpressing mice (gankyrin(hep)) exhibited malignant transformation from liver fibrosis to tumors even under single CCl(4) administration, whereas wild-type mice merely experienced fibrosis. Consistently, enhanced hepatic injury, severe inflammation and strengthened compensatory proliferation occurred in gankyrin(hep) mice during CCl(4) performance. This correlated with augmented expressions of cell cycle-related genes and abnormal activation of Rac1/c-jun N-terminal kinase (JNK). Pharmacological inhibition of the Rac1/JNK pathway attenuated hepatic fibrosis and prevented CCl(4)-induced carcinogenesis in gankyrin(hep) mice. Together, these findings suggest that gankyrin promotes liver fibrosis/cirrhosis progression into hepatocarcinoma relying on a persistent liver injury and inflammatory microenvironment. Blockade of Rac1/JNK activation impeded gankyrin-mediated hepatocytic malignant transformation, indicating the combined inhibition of gankyrin and Rac1/JNK as a potential prevention mechanism for cirrhosis transition.