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ß-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma

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收录情况： ◇ SCIE

作者：
Zhang, Yi[1,2,3] * ; Xu, Hongwei[4] ; Cui, Guofei[2,3] ; Liang, Binyong[5] ; Chen, Xiangzheng[6,7] ; Ko, Sungjin[8,9,10] ; Affo, Silvia[11] ; Song, Xinhua[12] ; Liao, Yi[13] ; Feng, Jianguo[14,15] ; Wang, Pan[16] ; Wang, Haichuan[2,3,6,7] ; Xu, Meng[17] ; Wang, Jingxiao[18] ; Pes, Giovanni M.[19] ; Ribback, Silvia[20] ; Zeng, Yong[6,7] ; Singhi, Aatur[8,9,10] ; Schwabe, Robert F.[21] ; Monga, Satdarshan P.[8,9,10] ; Evert, Matthias[22] ; Tang, Liling[1] ; Calvisi, Diego F.[22] ; Chen, Xin[2,3,23] ;
单位： [1]Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China [2]Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA [3]Univ Calif San Francisco, Liver Ctr, San Francisco, CA 94143 USA [4]Sichuan Univ, Ctr Liver Transplantat, Dept Liver Surg, West China Hosp, Chengdu, Sichuan, Peoples R China [5]Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr,Dept Surg, Wuhan, Peoples R China [6]Sichuan Univ, West China Hosp, Dept Liver Surg, Liver Transplantat Div, Chengdu, Peoples R China [7]Sichuan Univ, West China Hosp, Lab Liver Surg, Chengdu, Peoples R China [8]Univ Pittsburgh, Sch Med, Dept Pathol & Med, Pittsburgh, PA USA [9]Univ Pittsburgh, Sch Med, Pittsburgh Liver Res Ctr, Pittsburgh, PA USA [10]Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA [11]Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain [12]Capital Med Univ, Sch Tradit Chinese Med, Beijing, Peoples R China [13]Shenzhen Univ, Cent Lab, Hlth Sci Ctr, Shenzhen Peoples Hosp 2,Affiliated Hosp 1, Shenzhen, Guangdong, Peoples R China [14]Southwest Med Univ, Affiliated Hosp, Dept Anesthesiol, Luzhou, Peoples R China [15]Southwest Med Univ, Lab Anesthesiol, Luzhou, Peoples R China [16]Beijing Acad Agr & Forestry Sci, Beijing Vegetable Res Ctr, Collaborat Innovat Ctr Agr Prod Proc & Nutr & Hlt, Beijing, Peoples R China [17]Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Gen Surg, Xian, Peoples R China [18]Beijing Univ Chinese Med, Sch Life Sci, Beijing, Peoples R China [19]Univ Sassari, Dept Med Surg & Expt Sci, Sassari, Italy [20]Univ Greifswald, Inst Pathol, Greifswald, Germany [21]Columbia Univ, Dept Med, New York, NY USA [22]Univ Regensburg, Inst Pathol, Franz Josef Str Allee 11, D-93053 Regensburg, Germany [23]Univ Hawaii, Canc Biol Program, Canc Ctr, Honolulu, HI 96813 USA
出处：
DOI： 10.1053/j.gastro.2022.04.028
ISSN：

关键词： ss-Catenin Hippo/YAP Intrahepatic Cholangiocarcinoma TEADs

摘要：
BACKGROUND & AIMS: YES-associated protein (YAP) aberrant activation is implicated in intrahepatic cholangiocarcinoma (iCCA). Transcriptional enhanced associate domain (TEAD)-mediated transcriptional regulation is the primary signaling event downstream of YAP. The role of Wnt/ss-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and ss-Catenin cascades in iCCA. METHODS: Activated AKT (Myr-Akt) was coexpressed with YAP (YapS127A) or Tead2VP16 via hydrodynamic tail vein injection into mouse livers. Tumor growth was monitored, and liver tissues were collected and analyzed using histopathologic and molecular analysis. YAP, ss-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine ss-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or ss-Catenin. Immunostaining of total and nonphosphorylated/ activated ss-Catenin staining was performed in mouse and human iCCAs. RESULTS: We discovered that TEAD factors are required for YAP-dependent iCCA development. However, transcriptional activation of TEADs did not fully recapitulate YAP's activities in promoting cholangiocarcinogenesis. Notably, b-Catenin physically interacted with YAP in human and mouse iCCA. Ctnnb1 ablation strongly suppressed human iCCA cell growth and Yap-dependent cholangiocarcinogenesis. Furthermore, RNA-sequencing analysis revealed that YAP/ transcriptional coactivator with PDZ-binding motif (TAZ) regulate a set of genes significantly overlapping with those controlled by ss-Catenin. Importantly, activated/nonphosphorylated ss-Catenin was detected in more than 80% of human iCCAs. CONCLUSION: YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with ss-Catenin. ss-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and ss-Catenin pathways in cholangiocarcinogenesis.

基金：
National Institutes of Health [R01CA19606, R01CA228483, R01CA204586, R01CA250227, R01CA258449]; UCSF Liver Center [P30DK026743]; Pittsburgh Liver Research Center [P30DK120531]; Natural Science Foundation of Chongqing [2021ycjh-bgzxm0169, cstc2021jcyj-cxttX0002cstc]
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
JCR分区：
出版当年[2020]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[2020版] 出版当年五年平均 出版前一年[2019版] 出版后一年[2021版]

第一作者：
第一作者单位： [1]Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China [2]Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA [3]Univ Calif San Francisco, Liver Ctr, San Francisco, CA 94143 USA
通讯作者：
通讯机构： [2]Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA [3]Univ Calif San Francisco, Liver Ctr, San Francisco, CA 94143 USA [23]Univ Hawaii, Canc Biol Program, Canc Ctr, Honolulu, HI 96813 USA
推荐引用方式(GB/T 7714)：
Zhang Yi,Xu Hongwei,Cui Guofei,et al.ß-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma[J].GASTROENTEROLOGY.2022,163(2):481-494.doi:10.1053/j.gastro.2022.04.028.
APA：
Zhang, Yi,Xu, Hongwei,Cui, Guofei,Liang, Binyong,Chen, Xiangzheng...&Chen, Xin.(2022).ß-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma.GASTROENTEROLOGY,163,(2)
MLA：
Zhang, Yi,et al."ß-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma".GASTROENTEROLOGY 163..2(2022):481-494

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