文献类型： 外文期刊

作者： Zhang, Yi ¹ ; Xu, Hongwei ⁴ ; Cui, Guofei ² ; Liang, Binyong ⁵ ; Chen, Xiangzheng ⁶ ; Ko, Sungjin ⁸ ; Affo, Silvia ¹¹ ; Song, Xinhua ¹² ; Liao, Yi ¹³ ; Feng, Jianguo ¹⁴ ; Wang, Pan ¹⁶ ; Wang, Haichuan ² ; Xu, Meng ¹⁷ ; Wang, Jingxiao ¹⁸ ; Pes, Giovanni M. ¹⁹ ; Ribback, Silvia ²⁰ ; Zeng, Yong ⁶ ; Singhi, Aatur ⁸ ; Schwabe, Robert F. ²¹ ; Monga, Satdarshan P. ⁸ ; Evert, Matthias ²² ; Tang, Liling ¹ ; Calvisi, Diego F. ²² ; Chen, Xin ² ;

作者机构： 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

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

期刊名称：GASTROENTEROLOGY （ 影响因子：33.883； 五年影响因子：29.175 ）

ISSN： 0016-5085

年卷期： 2022 年 163 卷 2 期

页码：

收录情况： SCI

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.