Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation-driven hepatocarcinogenesis

• Published in: Hepatology (Baltimore, Md.) Vol. 77; no. 6; pp. 1929 - 1942
• Main Authors: Liang, Binyong, Wang, Haichuan, Qiao, Yu, Wang, Xue, Qian, Manning, Song, Xinhua, Zhou, Yi, Zhang, Yi, Shang, Runze, Che, Li, Chen, Yifa, Huang, Zhiyong, Wu, Hong, Monga, Satdarshan P., Zeng, Yong, Calvisi, Diego F., Chen, Xiaoping, Chen, Xin
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.06.2023
• Subjects: Animals; Axin Protein - genetics; beta Catenin - genetics; Carcinogenesis - genetics; Carcinoma, Hepatocellular - pathology; Humans; Liver Neoplasms - pathology; Mice; Mutation; Protein Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.32693

Background and Aims: Gain-of-function (GOF) mutations of CTNNB1 and loss-of-function (LOF) mutations of AXIN1 are recurrent genetic alterations in hepatocellular carcinoma (HCC). We aim to investigate the functional contribution of Hippo/YAP/TAZ in GOF CTNNB1 or LOF AXIN1 mutant HCCs. Approach and Results: The requirement of YAP/TAZ in c-Met/β-Catenin and c-Met/sgAxin1-driven HCC was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. Mechanisms of AXIN1 in regulating YAP/TAZ were investigated using AXIN1 mutated HCC cells. Hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of Yap;Taz during tumor progression. Cabozantinib and G007-LK combinational treatment were tested in vitro and in vivo. Nuclear YAP/TAZ was strongly induced in c-Met/sgAxin1 mouse HCC cells. Activation of Hippo via overexpression of Lats2 or concomitant deletion of Yap and Taz significantly inhibited c-Met/sgAxin1 driven HCC development, whereas the same approaches had mild effects in c-Met/β-Catenin HCCs. YAP is the major Hippo effector in c-Met/β-Catenin HCCs, and both YAP and TAZ are required for c-Met/sgAxin1-dependent hepatocarcinogenesis. Mechanistically, AXIN1 binds to YAP/TAZ in human HCC cells and regulates YAP/TAZ stability. Genetic deletion of YAP/TAZ suppresses already formed c-Met/sgAxin1 liver tumors, supporting the requirement of YAP/TAZ during tumor progression. Importantly, tankyrase inhibitor G007-LK, which targets Hippo and Wnt pathways, synergizes with cabozantinib, a c-MET inhibitor, leading to tumor regression in the c-Met/sgAxin1 HCC model. Conclusions: Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ is an effective treatment against AXIN1 mutant human HCCs.