LIM and SH3 protein 1 (Lasp1) is a novel p53 transcriptional target involved in hepatocellular carcinoma
LIM and SH3 protein 1 (Lasp1) is a novel p53 transcriptional target involved in hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2008.10.025
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发表时间：
2009-03-01
影响因子：
25.7
通讯作者：
Ren, Ee-Chee
中科院分区：
文献类型：
--
作者：
Wang, Bei;Feng, Ping;Ren, Ee-Chee
背景/目标：肝细胞癌（HCC）是世界范围内癌症相关死亡的主要原因之一，与肿瘤浸润和转移相关的预后不良。肿瘤抑制基因p53在肿瘤的发生发展中起着关键作用，但越来越多的证据表明其参与肿瘤转移，其潜在的机制在很大程度上未被探索。方法：利用p53结合数据库与HCC微阵列表达谱的组合分析，我们确定了一个新的转移相关基因Lasp 1作为潜在的p53靶点。在这项研究中，我们证明，Lasp 1确实是一个真正的p53的目标，通过验证的功能抑制作用的p53 Lasp 1通过p53的反应元件。瞬时转染野生型p53而非突变型p53抑制Hep 3B（p53-/-）细胞中的Lasp 1，而p53 siRNA上调HepG 2（p53+/+）细胞中的Lasp 1表达。参与DNA结合的关键残基处的p53突变消除了p53介导的对Lasp 1表达的抑制。此外，Lasp 1调节肝癌细胞的生长以及细胞的迁移和invasions.Conclusions：p53转录抑制Lasp 1，这是一个伙伴蛋白在影响肝癌细胞的运动。这表明p53可能通过Lasp 1影响肿瘤转移。(C)2008年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with poor prognosis associated with tumor invasion and metastasis. The tumor suppressor p53 plays critical roles in tumor development, but there is increasing evidence for its involvement in tumor metastasis with the underlying mechanisms largely unexplored.Methods: Using combinatorial analysis of a p53 binding database with HCC microarray expression profile, we identified a novel metastasis-related gene Lasp1 as a potential p53 target.Results: In this study, we demonstrate that Lasp1 is indeed a bona fide p53 target by validating the functional repression effect of p53 on Lasp1 via a p53 response element. Transient transfection of wild-type p53 but not the mutant form suppressed Lasp1 in Hep3B (p53-/-) cells, while p53 siRNA up-regulated its expression in HepG2 (p53+/+) cells. p53 mutations at key residues involved in DNA binding abrogates the p53-mediated suppression of Lasp1 expression. In addition, Lasp1 regulates HCC cell growth as well as cell migration and invasion ability.Conclusions: p53 transcriptionally represses Lasp1, which is a partner protein in affecting HCC cell motility. This suggests that p53 may play a role in influencing tumor metastasis through Lasp1. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.