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TAZ is indispensable for c-MYC-induced hepatocarcinogenesis.

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机构： [1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China [2]Laboratory of LiverSurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China [3]Department of Bioengineering and Therapeutic Sciences andLiver Center, University of California, San Francisco, California, USA [4]Department of Oncology and Hematology, the Second Hospital, JilinUniversity, Changchun, China [5]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China [6]School of Pharmacy, HubeiUniversity of Chinese Medicine Wuhan, Hubei, China [7]Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis andTranslational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, People’s Republic of China [8]Instituteof Pathology, University of Greifswald, Greifswald, Germany [9]Institute of Pathology, University of Regensburg, Regensburg, Germany [10]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology,Wuhan, China

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Mounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ during c-MYC induced liver tumor development.YAP and/or TAZ requirement for c-Myc driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. Hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples.We found that the Hippo cascade is inactivated in c-Myc induced mouse HCC. Intriguingly, TAZ, but not YAP mRNA levels and TAZ activation status, correlated with c-MYC activity in human and mouse HCC. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc HCC progression.TAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of HCC patients with c-MYC activation.We identified TAZ as a transcriptional c-MYC target and the TAZ/BCL2L12 axis as a critical anti-apoptotic effector in c-MYC dependent hepatocarcinogenesis.Copyright © 2021. Published by Elsevier B.V.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

第一作者：

第一作者机构： [1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China [2]Laboratory of LiverSurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China [3]Department of Bioengineering and Therapeutic Sciences andLiver Center, University of California, San Francisco, California, USA

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通讯机构： [1]Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China [2]Laboratory of LiverSurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China [3]Department of Bioengineering and Therapeutic Sciences andLiver Center, University of California, San Francisco, California, USA [9]Institute of Pathology, University of Regensburg, Regensburg, Germany [*1]Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, [*2]Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan 610041, China [*3]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143, USA

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