Haichuan Wang1,2,3, Xinhua Song3, Haotian Liao1,2, Pan Wang3, Yi Zhang3, Li Che3, Jie Zhang4, Yi Zhou3, Antonio Cigliano5, Cindy Ament5, Daphne Superville6, Silvia Ribback7, Melissa Reeves6, Giovanni M Pes8, Binyong Liang9, Hong Wu1,2, Matthias Evert5, Diego F Calvisi5, Yong Zeng1,2, Xin Chen3. 1. Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China. 2. Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 3. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA. 4. Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. 5. Institute of Pathology, University of Regensburg, Regensburg, Germany. 6. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA. 7. Institute of Pathology, University of Greifswald, Greifswald, Germany. 8. Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy. 9. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract
BACKGROUND AND AIMS: Mothers against decapentaplegic homolog (SMAD) 7 is an antagonist of TGF-β signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches. APPROACH AND RESULTS: We found that SMAD7 is up-regulated in a subset of human HCC samples with poor prognosis. Gene set enrichment analysis revealed that SMAD7 expression correlates with activated yes-associated protein (YAP)/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/myeloid cell leukemia 1 (MCL1)-induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, coexpression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly up-regulated, especially in the most aggressive tumors, and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. CONCLUSIONS: The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and inducing a cholangiocellular and EMT signature.
BACKGROUND AND AIMS: Mothers against decapentaplegic homolog (SMAD) 7 is an antagonist of TGF-β signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches. APPROACH AND RESULTS: We found that SMAD7 is up-regulated in a subset of human HCC samples with poor prognosis. Gene set enrichment analysis revealed that SMAD7 expression correlates with activated yes-associated protein (YAP)/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/myeloid cell leukemia 1 (MCL1)-induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, coexpression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly up-regulated, especially in the most aggressive tumors, and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. CONCLUSIONS: The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and inducing a cholangiocellular and EMT signature.
Authors: Richard S Finn; Shukui Qin; Masafumi Ikeda; Peter R Galle; Michel Ducreux; Tae-You Kim; Masatoshi Kudo; Valeriy Breder; Philippe Merle; Ahmed O Kaseb; Daneng Li; Wendy Verret; Derek-Zhen Xu; Sairy Hernandez; Juan Liu; Chen Huang; Sohail Mulla; Yulei Wang; Ho Yeong Lim; Andrew X Zhu; Ann-Lii Cheng Journal: N Engl J Med Date: 2020-05-14 Impact factor: 91.245
Authors: Chaobo Chen; Hanghang Wu; Hui Ye; Agustín Tortajada; Sandra Rodríguez-Perales; Raúl Torres-Ruiz; August Vidal; Maria Isabel Peligros; Johanna Reissing; Tony Bruns; Mohamed Ramadan Mohamed; Kang Zheng; Amaia Lujambio; Maria J Iraburu; Leticia Colyn; Maria Ujue Latasa; María Arechederra; Maite G Fernández-Barrena; Carmen Berasain; Javier Vaquero; Rafael Bañares; Leonard J Nelson; Christian Trautwein; Roger J Davis; Eduardo Martinez-Naves; Yulia A Nevzorova; Alberto Villanueva; Matias A Avila; Francisco Javier Cubero Journal: Cancers (Basel) Date: 2021-12-24 Impact factor: 6.639