The metastasis suppressor, NDRG1, inhibits "stemness" of colorectal cancer via down-regulation of nuclear β-catenin and CD44.
The metastasis suppressor, NDRG1, inhibits "stemness" of colorectal cancer via down-regulation of nuclear β-catenin and CD44.
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转移抑制因子 NDRG1 通过下调核 β-连环蛋白和 CD44 抑制结直肠癌的“干性”。
DOI：
10.18632/oncotarget.5294
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Zheng M
中科院分区：
文献类型：
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作者：
Wangpu X;Yang X;Zhao J;Lu J;Guan S;Lu J;Kovacevic Z;Liu W;Mi L;Jin R;Sun J;Yue F;Ma J;Lu A;Richardson DR;Wang L;Zheng M
N-myc下游调节基因1(NDRG1)是一种重要的结直肠癌转移抑制基因。在本研究中，我们研究了NDRG1在结直肠癌干性和肿瘤发生中的作用；(2)相关的分子机制；(3)NDRG1表达与结直肠癌预后的关系。我们的研究表明，沉默NDRG1的CRC细胞具有更强的致瘤能力和干细胞样特性，如：集落和球体形成、化疗耐药、细胞侵袭、CD44高表达和体内致瘤性。此外，β-Catenin在细胞膜上的表达减少，而在核上的表达增加。Ndr1的抗肿瘤活性是通过抑制β-连环蛋白的核转位来实现的，因为沉默后一种分子可以逆转沉默Ndr1表达的效果。NDRG1的表达与结直肠癌预后呈负相关。此外，在临床标本中，NDRG1CD44的表达与β-连环蛋白的表达呈负相关。综上所述，我们的研究表明，NDRG1在结直肠癌中的抗转移活性是通过下调核β-连环蛋白来实现的，并提示NDRG1是一个重要的治疗靶点。
N-myc downstream-regulated gene 1 (NDRG1), has been identified as an important metastasis suppressor for colorectal cancer (CRC). In this study, we investigated: (1) the effects of NDRG1 on CRC stemness and tumorigenesis; (2) the molecular mechanisms involved; and (3) the relationship between NDRG1 expression and colorectal cancer prognosis. Our investigation demonstrated that CRC cells with silenced NDRG1 showed more tumorigenic ability and stem cell-like properties, such as: colony and sphere formation, chemoresistance, cell invasion, high expression of CD44, and tumorigenicity in vivo. Moreover, NDRG1 silencing reduced β-catenin expression on the cell membrane, while increasing its nuclear expression. The anti-tumor activity of NDRG1 was demonstrated to be mediated by preventing β-catenin nuclear translocation, as silencing of this latter molecule could reverse the effects of silencing NDRG1 expression. NDRG1 expression was also demonstrated to be negatively correlated to CRC prognosis. In addition, there was a negative correlation between NDRG1 and nuclear β-catenin and also NDRG1 and CD44 expression in clinical CRC specimens. Taken together, our investigation demonstrates that the anti-metastatic activity of NDRG1 in CRC occurs through the down-regulation of nuclear β-catenin and suggests that NDRG1 is a significant therapeutic target.