NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity.
NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity.
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NDRG1 通过调节 CDC42 活性来调节丝状伪足诱导的结直肠癌侵袭性
DOI：
10.7150/ijbs.56694
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发表时间：
2021
影响因子：
9.2
通讯作者：
Zheng M
中科院分区：
文献类型：
--
作者：
Aikemu B;Shao Y;Yang G;Ma J;Zhang S;Yang X;Hong H;Yesseyeva G;Huang L;Jia H;Wang C;Zang L;Sun J;Zheng M
N-myc下游调控基因-1 （NDRG1）已被确定为一种推定的转移抑制基因，并在我们之前的工作中被证明是癌症扩散和增殖的关键参与者。然而，NDRG1对肿瘤侵袭的影响及其背后的机制很少被了解。在这里，我们提供了计算机证据，证明NDRG1在结直肠癌（CRC）的肌动蛋白重组中起关键作用。通过体外实验，我们接下来观察到ndrg1修饰的细胞系中丝状足的形成发生了改变，而ndrg1沉默的细胞中细胞分裂周期42 （CDC42）过度激活。机制上，NDRG1缺失破坏RhoGDIα与CDC42之间的结合，触发CDC42的活化和下游级联PAK1/Cofilin，从而促进CRC丝状足的形成和侵袭性。NDRG1的敲低导致CRC细胞在体内的传播增强，并与CDC42的活性表达相关。通过临床样本分析，我们发现晚期T期患者CDC42活性水平升高，且与NDRG1表达呈负相关。总之，这些结果揭示了NDRG1在协调细胞骨架重组中调节CDC42活性的机制，这在癌症侵袭中至关重要。
N-myc downstream regulated gene-1 (NDRG1) has been identified as a putative metastasis suppressor gene and proved to be a key player in cancer spreading and proliferation in our previous work. However, the effects of NDRG1 on tumor invasion and the mechanisms behind it are rarely understood. Here we provided in silico evidence that NDRG1 plays a crucial role in actin reorganization in colorectal cancer (CRC). Through in vitro experiments, we next observed filopodia formation was altered in NDRG1-modified cell lines, while cell division cycle-42 (CDC42) displayed excessive activation in NDRG1-silenced cells. Mechanistically, NDRG1 loss disrupts the binding between RhoGDIα and CDC42 and triggers the activation of CDC42 and the downstream cascades PAK1/Cofilin, thereby promotes the formation of filopodia and invasiveness of CRC. The knockdown of NDRG1 led to enhanced dissemination of CRC cells in vivo and correlates with active CDC42 expression. Using clinical sample analysis, we found an elevated level of active CDC42 in patients with advanced T stage, and it was negatively related to NDRG1 expression. In sum, these results uncover a mechanism utilized by NDRG1 to regulate CDC42 activity in coordinating cytoskeleton reorganization, which was crucial in cancer invasion.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
El-Sibai, Mirvat;Pertz, Olivier;Backer, Jonathan M.
通讯作者：
Backer, Jonathan M.
影响因子：
7.5
作者：
Jacquemet, Guillaume;Hamidi, Hellyeh;Ivaska, Johanna
通讯作者：
Ivaska, Johanna
影响因子：
8.1
作者：
Luna Vital, Diego A.;Loarca-Pina, Guadalupe;Gonzalez de Mejia, Elvira
通讯作者：
Gonzalez de Mejia, Elvira
影响因子：
11.2
作者：
Maldonado MDM;Dharmawardhane S
通讯作者：
Dharmawardhane S