Tcf7l1 Acts as a Suppressor for the Self-Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of β-Catenin
Tcf7l1 Acts as a Suppressor for the Self-Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of β-Catenin
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Tcf7l1 作为肝癌干细胞自我更新的抑制剂，并受 IGF/MEK/ERK 信号传导的调节，独立于 β-Catenin
DOI：
10.1002/stem.3063
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发表时间：
2019-08-26
期刊：
影响因子：
5.2
通讯作者：
Qian, Cheng
中科院分区：
文献类型：
--
作者：
Shan, Juanjuan;Shen, Junjie;Qian, Cheng
Tcf 7 l1是Wnt/β-连环蛋白信号通路的关键效应分子，在各种癌症中高度表达，并且它促进肿瘤生长。在这项研究中，我们证明，与其他几种类型的癌症中的肿瘤促进作用不同，Tcf 7 l1在肝癌中的表达与相邻的非肿瘤对应物相比下调。Tcf 7 l1的低表达与较差的生存相关。在肝癌干细胞（CSC）群体中，Tcf 7 l1表达下调。Tcf 7 l1的异位表达减弱肝CSCs的自我更新能力从机制上讲，Tcf 7 l1通过Nanog基因的转录抑制来调节肝CSC的自我更新能力，并且该作用不依赖于β-连环蛋白。此外，我们发现Tcf 7 l1的表达受细胞外胰岛素样生长因子（IGF）信号的调控，并首次证实IGF信号通过丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）途径刺激Tcf 7 l1的磷酸化和降解。总的来说，我们的研究结果为细胞外信号如何调节肝脏CSC的自我更新提供了一些新的见解，并突出了Tcf 7 l1在癌症中的抑制作用。干细胞2019
Tcf7l1, which is a key effector molecule of the Wnt/beta-catenin signaling pathway, is highly expressed in various cancers, and it promotes tumor growth. In this study, we demonstrated that unlike its tumor-promoting effects in several other types of cancers, Tcf7l1 expression is downregulated in hepatocarcinoma compared with their adjacent nontumor counterparts. Underexpression of Tcf7l1 is correlated with poorer survival. In liver cancer stem cell (CSC) populations, Tcf7l1 expression is downregulated. Ectopic expression of Tcf7l1 attenuates the self-renewal abilities of liver CSCs. Mechanistically, Tcf7l1 regulates the self-renewal abilities of liver CSCs through transcriptional repression of the Nanog gene, and the effect is independent of beta-catenin. Moreover, we found that Tcf7l1 expression is controlled by extracellular insulin-likegrowth factor (IGF) signaling, and we demonstrated for the first time that IGF signaling stimulates Tcf7l1 phosphorylation and degradation through the mitogen-activated protein kinase (MEK)/extracellularsignal-regulated kinase (ERK) pathway. Overall, our results provide some new insights into how extracellular signals modulate the self-renewal of liver CSCs and highlight the inhibitory roles of Tcf7l1 in cancer. Stem Cells 2019