{"doi":"10.1002/hep.32693","title":"Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation‐driven hepatocarcinogenesis","abstract":"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-CreER T2KO 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.","journal":"Hepatology","year":2022,"id":249019,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302531,"name":"Haichuan Wang","orcid":"0000-0002-6886-5698","position":1,"is_corresponding":false},{"id":889083,"name":"Yu Qiao","orcid":"0000-0002-0374-5089","position":2,"is_corresponding":false},{"id":519121,"name":"Xue Wang","orcid":"0000-0002-2381-9145","position":3,"is_corresponding":false},{"id":450690,"name":"Manning Qian","orcid":null,"position":4,"is_corresponding":false},{"id":278049,"name":"Xinhua Song","orcid":"0000-0002-8232-6869","position":5,"is_corresponding":false},{"id":278051,"name":"Yi Zhou","orcid":"0000-0001-9024-7514","position":6,"is_corresponding":false},{"id":846702,"name":"Yi Zhang","orcid":"0000-0001-6223-4724","position":7,"is_corresponding":false},{"id":278048,"name":"Runze Shang","orcid":"0000-0002-7958-0700","position":8,"is_corresponding":false},{"id":1351,"name":"Li Che","orcid":"0000-0001-7971-8725","position":9,"is_corresponding":false},{"id":658176,"name":"Yifa Chen","orcid":"0000-0002-1718-6871","position":10,"is_corresponding":false},{"id":658178,"name":"Zhiyong Huang","orcid":"0000-0002-2239-0674","position":11,"is_corresponding":false},{"id":469053,"name":"Hong Wu","orcid":"0000-0002-0885-4911","position":12,"is_corresponding":false},{"id":277667,"name":"Satdarshan P. 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