The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells.
The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells.
复制标题
NKD1/Rac1反馈环路调控肝癌细胞的侵袭和迁移能力
DOI：
10.1038/srep26971
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发表时间：
2016-05-27
影响因子：
4.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Li J;Zhang S;Hu Q;Zhang K;Jin J;Zheng X;Yin Z;Wang X
肝细胞癌（HCC）具有侵袭性和转移性，是导致HCC患者死亡率增加的主要原因。NKD 1蛋白在许多肿瘤中异常表达，并在肿瘤进展中起重要作用。然而，NKD 1在HCC细胞侵袭和迁移中的调控和潜在的分子机制仍然知之甚少。在本研究中，NKD 1在肝癌细胞中的异位表达通过下调Rac 1的表达水平和活性，从而影响肝癌细胞的细胞骨架和E-cadherin的表达，从而减弱肝癌细胞在体外和体内的迁移和侵袭。机制研究表明，NKD 1与Rac 1在细胞质中相互作用，并通过泛素-蛋白酶体途径促进其降解。Rac 1的过表达可促进NKD 1基因的转录，而EZH 2的负调控作用则相反。临床标本分析显示NKD 1和Rac 1的异常表达与HCC患者的不良预后相关。总之，我们的数据表明NKD 1通过涉及Rac 1的反馈回路作为HCC细胞侵袭和迁移的调节剂的新作用。
Hepatocellular carcinoma (HCC) is complicated by aggressive migration and invasion, which contribute to the increased mortality of HCC patients. The NKD1 protein is abnormally expressed in many neoplasms and plays an important role in tumor progression. However, the regulation and underlying molecular mechanisms of NKD1 in HCC cell invasion and migration remain poorly understood. In the present study, ectopic expression of NKD1 in HCC cells attenuated migration and invasionin vitroandin vivoby down-regulating Rac1 expression level and activity, which affected the HCC cell cytoskeleton and E-cadherin expression. Mechanistic studies showed that NKD1 interacted with Rac1 in the cytoplasm and promoted its degradation by the ubiquitin-proteasome pathway. Over-expression of Rac1 enhanced the transcription of theNKD1gene and protein expression conversely owing to its negative regulation of EZH2. Analysis of clinical samples showed that abnormal expression of NKD1 and Rac1 was associated with the poor prognosis of HCC patients. In summary, our data indicate a new role for NKD1 as a regulator of HCC cell invasion and migration via a feedback loop involving Rac1.