Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling.
Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling.
复制标题
肝癌的发生需要通过 CD44 增强的生长因子信号传导抑制 p53
DOI：
10.1016/j.ccell.2018.05.003
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发表时间：
2018-06-11
期刊：
影响因子：
50.3
通讯作者：
Karin M
中科院分区：
文献类型：
--
作者：
Dhar D;Antonucci L;Nakagawa H;Kim JY;Glitzner E;Caruso S;Shalapour S;Yang L;Valasek MA;Lee S;Minnich K;Seki E;Tuckermann J;Sibilia M;Zucman-Rossi J;Karin M
经历致癌性损伤的完全分化的细胞如何成为获得多个起始突变的增殖性癌症祖细胞尚不清楚。这个问题是特别相关的肝细胞癌（HCC），这是由分化的肝细胞。在这里，我们表明，这个问题的一个解决方案是由CD44，透明质酸受体，其表达是迅速诱导致癌物暴露的肝细胞中的STAT3依赖性的方式。一旦表达，CD44增强AKT活化以诱导Mdm 2的磷酸化和核转位，其终止p53基因组监视应答。这使得DNA损伤的肝细胞能够逃避p53诱导的死亡和衰老，并对增殖信号做出反应，这些增殖信号促进突变的固定及其传递到继续成为HCC祖细胞的子细胞。达尔等人表明，在致癌物暴露的肝细胞中诱导的CD 44表达增强AKT信号传导以激活Mdm 2，其终止p53基因组监视应答。这使得DNA损伤的肝细胞对增殖信号做出反应，导致它们的子细胞成为HCC祖细胞。
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors. Dhar et al. show that CD44 expression induced in carcinogen-exposed hepatocytes potentiates AKT signaling to activate Mdm2, which terminates the p53 genomic surveillance response. This allows DNA damaged hepatocytes to respond to proliferative signals, leading their daughter cells to become HCC progenitors.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
64.5
作者：
He G;Dhar D;Nakagawa H;Font-Burgada J;Ogata H;Jiang Y;Shalapour S;Seki E;Yost SE;Jepsen K;Frazer KA;Harismendy O;Hatziapostolou M;Iliopoulos D;Suetsugu A;Hoffman RM;Tateishi R;Koike K;Karin M
通讯作者：
Karin M
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.
影响因子：
4.8
作者：
Chakrabarti, SK;James, JC;Mirmira, RG
通讯作者：
Mirmira, RG
影响因子：
5.4
作者：
Aubrey, Brandon J.;Strasser, Andreas;Kelly, Gemma L.
通讯作者：
Kelly, Gemma L.