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Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis.

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收录情况： ◇ SCIE

作者：
Jingxiao Wang[1,3] ; Haichuan Wang[2,3,11] ; Michele Peters[4] ; Ning Ding[5] ; Silvia Ribback[4] ; Kirsten Utpatel[6] ; Antonio Cigliano[4,6] ; Frank Dombrowski[4] ; Meng Xu[3,7] ; Xinyan Chen[3,8] ; Xinhua Song[3] ; Li Che[3] ; Matthias Evert[6] ; Antonio Cossu[9] ; John Gordan[10] ; Yong Zeng[2,11,*2] ; Xin Chen[3,*1] ; Diego F. Calvisi[4,6,*3] ;
机构： [1]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China [2]Department of Liver Surgery, Liver Transplantation Division,West China Hospital, Sichuan University, Chengdu, China [3]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, United States [4]Institute of Pathology, University of Greifswald, Greifswald, Germany [5]Department ofGastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China [6]Institute of Pathology,University of Regensburg, Regensburg, Germany [7]Department of General Surgery, The Second Hospital of Xi’an Jiaotong University,Xi’an Jiaotong University, Xi’an, China [8]Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China [9]Unit of Pathology,Azienda Ospedaliero Universitaria Sassari, Sassari, Italy [10]Department of Medicine, University of California, San Francisco, CA, United States [11]Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
出处：
DOI： 10.1016/j.jhep.2019.05.027
ISSN：

关键词： FBXW7 Cholangiocarcinogenesis c-Myc Cholangiocarcinoma murine model Yap Notch2

摘要：
The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA). Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens. FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of Fbxw7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-MYC was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-MYC transcriptional activity was observed. Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-MYC might represent an innovative therapy against iCCA exhibiting low FBXW7 expression. There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma. Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

基金：
This study is supported by NIH grants R01CA190606 to XC, P30DK026743 for UCSF Liver Center; grant from the Deutsche Forschungsgemeinschaft DFG (grant number RI2695/1-1) to SR, China Scholarship Council State Scholarship Fund No. 201606240132 to HW and Grants from National Natural Science Foundation of China (grant number 61006403) to YZ. Additional support was provided by the Helen Diller Family Comprehensive Cancer Center Director’s Fund.
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外文
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出版当年[2019]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[2019]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[2019版] 出版当年五年平均 出版前一年[2018版] 出版后一年[2020版]

第一作者：
第一作者机构： [1]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China [3]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, United States
共同第一作者：
通讯作者：
通讯机构： [2]Department of Liver Surgery, Liver Transplantation Division,West China Hospital, Sichuan University, Chengdu, China [3]Department of Bioengineering and Therapeutic Sciences and Liver Center,University of California, San Francisco, CA, United States [4]Institute of Pathology, University of Greifswald, Greifswald, Germany [6]Institute of Pathology,University of Regensburg, Regensburg, Germany [11]Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China [*1]UCSF, 513 Parnassus Avenue, San Francisco, CA 94143, USA [*2]Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan, China [*3]Institute of Pathology, University of Regensburg, Franz-Joseph-Strauss Allee 11, 93053 Regensburg, Germany
推荐引用方式(GB/T 7714)：
Jingxiao Wang,Haichuan Wang,Michele Peters,et al.Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis.[J].JOURNAL OF HEPATOLOGY.2019,71(4):742-752.doi:10.1016/j.jhep.2019.05.027.
APA：
Jingxiao Wang,Haichuan Wang,Michele Peters,Ning Ding,Silvia Ribback...&Diego F. Calvisi.(2019).Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis..JOURNAL OF HEPATOLOGY,71,(4)
MLA：
Jingxiao Wang,et al."Loss of Fbxw7 synergizes with activated Akt signaling to promote c-Myc dependent cholangiocarcinogenesis.".JOURNAL OF HEPATOLOGY 71..4(2019):742-752

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