机构：[1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China华中科技大学同济医学院附属同济医院[2]Department of Liver Surgery, Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[3]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA[4]Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China[5]Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA[6]National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China[7]School of Traditional Chinese Medicine, Capital Medical University, Beijing, China[8]Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China[9]Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China[10]Department of General Surgery, Affiliated Haixia Hospital of Huaqiao University (The 910 Hospital), Quanzhou, China[11]Legend Biotech USA, New Jersey, USA[12]Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA[13]Institute of Pathology, University of Regensburg, Regensburg 93053, Germany.[14]University of Hawaii Cancer Center, Hawaii, USA.
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.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.Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ as an effective treatment against AXIN1 mutant human HCCs.This article is protected by copyright. All rights reserved.
基金：
This study is supported by NIH grants R03CA208311, R01CA250227, and
R01CA239251 to Xin Chen, P30DK026743 for UCSF Liver Center; grants from China
Scholarship Council (grant number 201806165021) and Natural Science Foundation of Hubei
province (grant number 2017CFB258) to Binyong Liang, grants from National Natural Science
Foundation (grant number 82002967) to Haichuan Wang.
第一作者机构：[1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China[3]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA
共同第一作者：
通讯作者：
通讯机构：[1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China[2]Department of Liver Surgery, Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China[3]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA[14]University of Hawaii Cancer Center, Hawaii, USA.[*1]Department of Liver Surgery, Laboratory of Liver Surgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan 610041, China.[*2]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.[*3]University of Hawaii Cancer Center, Hawaii 96813, USA.
推荐引用方式(GB/T 7714)：
Binyong Liang,Haichuan Wang,Yu Qiao,et al.Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation driven hepatocarcinogenesis[J].HEPATOLOGY.2023,77(6):1929-1942.doi:10.1002/hep.32693.
APA：
Binyong Liang,Haichuan Wang,Yu Qiao,Xue Wang,Manning Qian...&Xin Chen.(2023).Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation driven hepatocarcinogenesis.HEPATOLOGY,77,(6)
MLA：
Binyong Liang,et al."Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation driven hepatocarcinogenesis".HEPATOLOGY 77..6(2023):1929-1942
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