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Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes‐Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans
Author(s) -
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
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31692
Subject(s) - carcinogenesis , cancer research , hccs , notch signaling pathway , biology , mcl1 , smad , signal transduction , downregulation and upregulation , microbiology and biotechnology , cancer , hepatocellular carcinoma , gene , genetics
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.