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TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis.

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收录情况： ◇ SCIE

作者：
Binyong Liang[1,2] ; Yi Zhou[2,3] ; Manning Qian[2,4] ; Meng Xu[2,5] ; Jingxiao Wang[2,6] ; Yi Zhang[2,7] ; Xinhua Song[2] ; Haichuan Wang[2,8] ; Shumei Lin[3] ; Chuanli Ren[9] ; Satdarshan P. Monga[10] ; Bruce Wang[11] ; Matthias Evert[12] ; Yifa Chen[1] ; Xiaoping Chen[1] ; Zhiyong Huang[1,*1] ; Diego F.Calvisi[12,*2] ; Xin Chen[2,*3] ;
机构： [1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, China [2]Department of Bioengineering and Therapeutic Sciences and Liver Center, Universityof California, San Francisco, San Francisco, CA, USA [3]Department of Infectious Diseases, The First Affiliated Hospital of Xi'an JiaotongUniversity, Xi'an, China [4]College of Clinical Medicine, Yangzhou University, Yangzhou, China [5]Department of Gastroenterology, The Second Hospital of Xi'an Jiaotong University,Xi'an, China [6]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China [7]Key Laboratory of Biorheological Science and Technology, Ministry of Education,College of Bioengineering, Chongqing University, Chongqing, China [8]Liver Transplantation Division, Department of Liver Surgery, West China Hospital,Sichuan University, Chengdu, China , Laboratory of Liver Surgery, West China Hospital,Sichuan University, Chengdu, China [9]Department of Laboratory Medicine, Clinical Medical College of Yangzhou University,Yangzhou, China [10]Department of Pathology and Medicine, University of Pittsburgh School of Medicine,Pittsburgh, Pennsylvania, USA [11]Department of Medicine and Liver Center, University of California San Francisco, SanFrancisco, CA, USA [12]Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
出处：
DOI： 10.1016/j.jhep.2021.01.044
ISSN：

关键词： Hepatocellular carcinoma T-Box Transcription Factor 3 β-Catenin HIPPO cascade

摘要：
Gain of function (GOF) mutation of CTNNB1 gene is one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-Catenin pathway and thought to be an oncogene mediating activated β-Catenin driven HCC formation. We evaluated TBX3 expression pattern in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-Catenin (c-Met/β-Catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro. A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased tumor growth gene expression signatures. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-Catenin driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-Catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3. Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes. Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

基金：
NIH grants R01CA239251 to XC; R01CA204586 and R01CA250227 to XC and SPM; P30DK026743 to UCSF Liver Center; K08DK101603 to BW; Burroughs Wellcome Fund Career Award for Medical Scientists to BW.
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外文
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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
JCR分区：
出版当年[2021]版：
Q1 GASTROENTEROLOGY & HEPATOLOGY
最新[2023]版：
Q1 GASTROENTEROLOGY & HEPATOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者机构： [1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, China [2]Department of Bioengineering and Therapeutic Sciences and Liver Center, Universityof California, San Francisco, San Francisco, CA, USA
通讯作者：
通讯机构： [1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, China [2]Department of Bioengineering and Therapeutic Sciences and Liver Center, Universityof California, San Francisco, San Francisco, CA, USA [12]Institute of Pathology, University of Regensburg, Regensburg 93053, Germany [*1]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology,Wuan, 430030, China. [*2]Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany [*3]Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, 94143, USA
推荐引用方式(GB/T 7714)：
Binyong Liang,Yi Zhou,Manning Qian,et al.TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis.[J].JOURNAL OF HEPATOLOGY.2021,75(1):120-131.doi:10.1016/j.jhep.2021.01.044.
APA：
Binyong Liang,Yi Zhou,Manning Qian,Meng Xu,Jingxiao Wang...&Xin Chen.(2021).TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis..JOURNAL OF HEPATOLOGY,75,(1)
MLA：
Binyong Liang,et al."TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis.".JOURNAL OF HEPATOLOGY 75..1(2021):120-131

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