Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans.
Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans.
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DOI：
10.1002/hep.31692
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Wang H;Song X;Liao H;Wang P;Zhang Y;Che L;Zhang J;Zhou Y;Cigliano A;Ament C;Superville D;Ribback S;Reeves M;Pes GM;Liang B;Wu H;Evert M;Calvisi DF;Zeng Y;Chen X
母亲抗十肢截瘫同源物7 （SMAD7）是转化生长因子β (TGF-β)信号的拮抗剂。在目前的研究中，我们试图通过体外和体内方法确定SMAD7在肝癌发生中的相关性。我们发现SMAD7在预后不良的人肝细胞癌（HCC）样本中表达上调。基因集富集分析（GSEA）显示，SMAD7的表达与hcc中激活的YAP/NOTCH通路和胆管细胞特征基因相关。这些发现在人类HCC细胞系中得到证实。在体内，单独过表达Smad7不能启动HCC的发展，但它能显著加速c-Myc/MCL1诱导的小鼠HCC的形成。与人类HCC数据一致，c-Myc/MCL1/Smad7肝肿瘤表现出胆管细胞基因表达增加，并伴有Yap/Notch激活和上皮-间质转化（EMT）。有趣的是，阻断Notch信号不会影响c-Myc/MCL1/ smad7诱导的肝癌发生，但会阻止胆管细胞特征表达和EMT，而Yap的消融会消除c-Myc/MCL1/ smad7驱动的HCC形成。在过表达肉鸡酰基化/活化形式的AKT的小鼠中，SMAD7的共表达加速了癌变，并将表型从HCC转变为肝内胆管癌（iCCA）病变。在人iCCA中，SMAD7的表达显著上调，特别是在最具侵袭性的肿瘤中，并且与YAP/NOTCH靶点以及胆管细胞和EMT标记物的水平直接相关。目前的数据表明，SMAD7通过激活YAP/NOTCH信号级联和诱导胆管细胞和EMT信号参与肝癌的发生。
Mothers against decapentaplegic homolog 7 (SMAD7) is an antagonist of the transforming growth factor β (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. We found that SMAD7 is upregulated in a subset of human hepatocellular carcinoma (HCC) samples with poor prognosis. Gene set enrichment analysis (GSEA) revealed that SMAD7 expression correlates with activated 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/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, co-expression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly upregulated, especially in the most aggressive tumors and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers. The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and by inducing a cholangiocellular and EMT signature.
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影响因子：
5.2
作者：
Personeni N;Lleo A;Pressiani T;Colapietro F;Openshaw MR;Stavraka C;Pouptsis A;Pinato DJ;Rimassa L
通讯作者：
Rimassa L
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影响因子：
29.4
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通讯作者：
Mishra L
影响因子：
64.5
作者：
Liu J;Lichtenberg T;Hoadley KA;Poisson LM;Lazar AJ;Cherniack AD;Kovatich AJ;Benz CC;Levine DA;Lee AV;Omberg L;Wolf DM;Shriver CD;Thorsson V;Cancer Genome Atlas Research Network;Hu H
通讯作者：
Hu H
影响因子：
13.8
作者：
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通讯作者：
Massague, Joan
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
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