Wang, Haichuan and Song, Xinhua and Liao, Haotian and Wang, Pan and Zhang, Yi and Che, Li and Zhang, Jie and Zhou, Yi and Cigliano, Antonio and Ament, Cindy and Superville, Daphne and Ribback, Silvia and Reeves, Melissa and Pes, Giovanni M. and Liang, Binyong and Wu, Hong and Evert, Matthias and Calvisi, Diego F. and Zeng, Yong and Chen, Xin (2021) Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans. HEPATOLOGY, 74 (1). pp. 248-263. ISSN 0270-9139, 1527-3350
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATOCELLULAR-CARCINOMA; SMAD7; GROWTH; EXPRESSION; CHOLANGIOCARCINOMA; RESISTANCE; MECHANISM; INTERACTS; CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Sep 2022 12:20 |
| Last Modified: | 20 Sep 2022 12:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47666 |
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