Overexpression of a Novel Activator of PAK4, the CDK5 Kinase-Associated Protein CDK5RAP3, Promotes Hepatocellular Carcinoma Metastasis
Overexpression of a Novel Activator of PAK4, the CDK5 Kinase-Associated Protein CDK5RAP3, Promotes Hepatocellular Carcinoma Metastasis
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DOI：
10.1158/0008-5472.can-10-4046
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Ching, Yick-Pang
中科院分区：
文献类型：
--
作者：
Mak, Grace Wing-Yan;Chan, Mandy Man-Lok;Ching, Yick-Pang
CDK 5激酶调节亚基相关蛋白3（CDK 5 RAP 3或C53/LZAP）调节遗传毒性应激诱导的细胞凋亡。虽然CDK 5 RAP 3与癌症进展有关，但其在致癌作用中的确切作用尚未完全确定。在这篇文章中，我们报告CDK 5 RAP 3在肝癌发生中具有重要的促转移功能。对人肝细胞癌（HCC）样本的检查显示，与相应的非肿瘤性肝脏相比，58%（39/67）的HCC样本中至少有两倍的CDK 5 RAP 3转录本过表达。CDK 5 RAP 3过表达与更具侵袭性的生物学行为相关。在HCC细胞系中，CDK 5 RAP 3的稳定过表达促进了肿瘤发生活性和转移潜能，而小干扰RNA介导的敲低抑制了肿瘤发生活性和转移潜能。我们发现，CDK 5 RAP 3和p21活化蛋白激酶4（PAK 4）的过度表达在人类HCC中相关，并且CDK 5 RAP 3是PAK 4的新结合伴侣，并且这种结合增强PAK 4活性。siRNA介导的PAK 4在表达CDK 5 RAP 3的HCC细胞中的敲低逆转了由CDK 5 RAP 3过表达介导的增强的细胞侵袭力，这意味着PAK 4对于CDK 5 RAP 3功能是必需的。总而言之，我们的研究结果表明CDK 5 RAP 3在HCC中广泛过表达，并且CDK 5 RAP 3的过表达通过PAK 4激活促进HCC转移。Cancer Res; 71（8）; 2949-58.（C）2011年《非洲标准化评论》。
The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA-mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. Cancer Res; 71(8); 2949-58. (C)2011 AACR.