Yi Zhang1, Hongwei Xu2, Guofei Cui3, Binyong Liang4, Xiangzheng Chen5, Sungjin Ko6, Silvia Affo7, Xinhua Song8, Yi Liao9, Jianguo Feng10, Pan Wang11, Haichuan Wang12, Meng Xu13, Jingxiao Wang14, Giovanni M Pes15, Silvia Ribback16, Yong Zeng5, Aatur Singhi6, Robert F Schwabe17, Satdarshan P Monga6, Matthias Evert18, Liling Tang19, Diego F Calvisi20, Xin Chen21. 1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California. 2. Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China. 3. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California. 4. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 5. Liver Transplantation Division, Department of Liver Surgery, and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. 6. Department of Pathology and Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 7. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 8. School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. 9. The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China. 10. Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Laboratory of Anesthesiology, Southwest Medical University, Luzhou, China. 11. Collaborative Innovation Center for Agricultural Product Processing and Nutrition & Health, Beijing Vegetable Research Center, Beijing Academy of Agriculture and Forestry Science, Beijing, China. 12. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Liver Transplantation Division, Department of Liver Surgery, and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. 13. Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China. 14. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. 15. Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy. 16. Institute of Pathology, University of Greifswald, Greifswald, Germany. 17. Department of Medicine, Columbia University, New York, New York. 18. Institute of Pathology, University of Regensburg, Regensburg, Germany. 19. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: tangliling@cqu.edu.cn. 20. Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de. 21. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii. Electronic address: xinchen3@hawaii.edu.
Abstract
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/β-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and β-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, β-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine β-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or β-Catenin. Immunostaining of total and nonphosphorylated/activated β-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, β-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 β-Catenin. Importantly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs. CONCLUSION: YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with β-Catenin. β-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.
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/β-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and β-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, β-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine β-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or β-Catenin. Immunostaining of total and nonphosphorylated/activated β-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, β-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 β-Catenin. Importantly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs. CONCLUSION: YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with β-Catenin. β-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.
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