NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis.
NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis.
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NDRG2通过Skp2-p21/p27轴的调节促进结直肠癌分化
DOI：
10.1038/s41388-017-0118-7
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Shen L;Qu X;Li H;Xu C;Wei M;Wang Q;Ru Y;Liu B;Xu Y;Li K;Hu J;Wang L;Ma Y;Li M;Lai X;Gao L;Wu K;Yao L;Zheng J;Zhang J
低分化结直肠癌(CRC)侵袭性更强，缺乏有针对性的治疗。我们和其他人之前报道了肿瘤抑制基因NDRG2在促进结直肠癌分化中的主要作用，但其潜在机制在很大程度上尚不清楚。在此，我们证明了NDRG2诱导结直肠癌细胞分化依赖于抑制E3连接酶Skp2的活性。在患者和Ndrg2基因敲除小鼠中，NDRG2和Skp2呈负相关，并与细胞分化阶段相关。此外，NDRG2抑制Skp2有助于诱导和稳定作为Skp2降解靶蛋白的p21和p27。通过shRNA下调p21和p27的表达，可以降低NDRG2诱导的AKP活性，恢复对细胞生长的抑制，因此NDRG2促进细胞分化的作用需要p21和p27。机制研究表明，NDRG2抑制β-连环蛋白的核转位，减少β-连环蛋白/Tcf复合体在Skp2启动子上的占有率，可能是通过使β去磷酸化。通过使一系列NDRG2缺失突变体接受Skp2的表达，NH2末端结构域的缺失可以完全取消NDRG2依赖的分化诱导。NDRG2低/Skp2高基因表达信号支持NDRG2和Skp2之间相互关系的生物学意义，与结直肠癌患者预后不良相关，可被认为是结直肠癌的诊断标志。
Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients andNdrg2knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses β-catenin nuclear translocation and decreases the occupancy of β-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3β. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH2-terminal domain can completely abolish NDRG2-dependent differentiation induction. Supporting the biological significance of the reciprocal relationship between NDRG2 and Skp2, an NDRG2low/Skp2highgene expression signature correlates with poor CRC patient outcome and could be considered as a diagnostic marker of CRCs.
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Lin HK
影响因子：
56.9
作者：
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通讯作者：
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影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
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