| Title | Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans |
| Authors | Wang, Haichuan Song, Xinhua Liao, Haotian Wang, Pan Zhang, Yi Che, Li Zhang, Jie Zhou, Yi Cigliano, Antonio Ament, Cindy Superville, Daphne Ribback, Silvia Reeves, Melissa Pes, Giovanni M. Liang, Binyong Wu, Hong Evert, Matthias Calvisi, Diego F. Zeng, Yong Chen, Xin |
| Affiliation | Sichuan Univ, West China Hosp, Liver Transplantat Div, Dept Liver Surg, 37 Guo Xue Xiang, Chengdu 610041, Peoples R China Sichuan Univ, West China Hosp, Lab Liver Surg, Chengdu, Sichuan, Peoples R China Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, 513 Parnassus Ave, San Francisco, CA 94143 USA Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94143 USA Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Dept Thorac Oncol 2,Key Lab Carcinogenesis & Tran, Beijing, Peoples R China Univ Regensburg, Inst Pathol, Franz Josef Str Allee 11, D-93053 Regensburg, Germany Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA Ernst Moritz Arndt Univ Greifswald, Inst Pathol, Greifswald, Germany Univ Sassari, Dept Med Surg & Expt Sci, Sassari, Italy Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr,Dept Surg, Wuhan, Peoples R China |
| Keywords | HEPATOCELLULAR-CARCINOMA SMAD7 GROWTH EXPRESSION CHOLANGIOCARCINOMA RESISTANCE MECHANISM INTERACTS CELLS |
| Issue Date | Jun-2021 |
| Publisher | HEPATOLOGY |
| Abstract | Background and Aims Mothers against decapentaplegic homolog (SMAD) 7 is an antagonist of TGF-beta 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. |
| URI | http://hdl.handle.net/20.500.11897/617799 |
| ISSN | 0270-9139 |
| DOI | 10.1002/hep.31692 |
| Indexed | SCI(E) |
| Appears in Collections: | 北京肿瘤医院 |
