TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition.
TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition.
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Lgr5 的 TAp63 α 介导结直肠癌干细胞特性和萝卜硫素抑制
DOI：
10.1038/s41389-020-00273-z
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发表时间：
2020-10-10
期刊：
影响因子：
6.2
通讯作者：
Zhong CY
中科院分区：
文献类型：
--
作者：
Chen Y;Wang MH;Zhu JY;Xie CF;Li XT;Wu JS;Geng SS;Han HY;Zhong CY
癌症干细胞（CSC）在癌症进展和治疗抗性中具有既定作用。p63蛋白属于p53家族，是重要的转录因子，但其在肿瘤干细胞中的功能和作用机制尚不清楚。在此，我们研究了TAp 63 α在结直肠CSCs中的作用以及萝卜硫素对TAp 63 α的影响。我们发现，与亲本细胞相比，TAp 63 α在具有干细胞特性的球体中上调。TAp 63 α的过表达促进了结肠直肠球形成细胞的自我更新能力和CSC标志物的表达。此外，我们发现TAp 63 α直接与Lgr 5的启动子区域结合，以增强其表达并激活其下游β-catenin通路。功能实验表明，萝卜硫素抑制结肠直肠CSCs的干细胞在体外和体内。TAp 63 α的上调减弱了莱菔硫烷对结直肠CSC的抑制作用，表明TAp 63 α在莱菔硫烷抑制结直肠癌中的干性中起作用。本研究首次阐明了TAp 63 α通过靶向Lgr 5/β-catenin轴促进CSCs的生长，并参与了莱菔硫烷对大肠癌干细胞特性的抑制。
Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.
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影响因子：
11.2
作者：
Rausch, Vanessa;Liu, Li;Herr, Ingrid
通讯作者：
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影响因子：
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作者：
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影响因子：
44.1
作者：
Li, Xiu-Bin;Yang, Guan;Teng, Yan
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Teng, Yan
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作者：
Rouleau, Matthieu;Medawar, Alain;Aberdam, Daniel
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影响因子：
8.8
作者：
Lin, C. W.;Li, X. R.;Zhang, Y.;Hu, G.;Guo, Y. H.;Zhou, J. Y.;Du, J.;Lv, L.;Gao, K.;Zhang, Y.;Deng, H.
通讯作者：
Deng, H.