Mechanisms of growth arrest by zinc ribbon domain-containing 1 in gastric cancer cells
Mechanisms of growth arrest by zinc ribbon domain-containing 1 in gastric cancer cells
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DOI：
10.1093/carcin/bgm064
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发表时间：
2007-08-01
期刊：
影响因子：
4.7
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Hong, Liu;Zhao, Yunping;Fan, Daiming
本实验室前期研究发现含锌带结构域I （ZNRD1）抑制胃癌细胞生长，细胞周期阻滞。然而，ZNRD1抑制生长作用的确切分子机制尚不清楚。在本研究中，我们已经证明ZNRD1可以显著抑制胃细胞系MKN28的体外和体内生长。利用人cDNA芯片、逆转录聚合酶链反应和western blot分析，鉴定过表达ZNRD1的MKN28细胞中差异表达的细胞周期相关基因。znrd1诱导的生长抑制至少部分调节了控制G向S进展的各种蛋白质和信号通路，包括抑制cyclin D1和CDK4，上调p21（CIP11WAF1）和p27（KiP1）以及加速pRb去磷酸化。此外，ZNRD1显著抑制cyclin D1的转录活性。p27（Kip1）可能在ZNRD1诱导的细胞周期阻滞中起关键作用，因为p27（Kip1）反义可以阻断ZNRD1的细胞抑制作用。此外，ZNRD1通过增加蛋白不稳定性来抑制Skp2的表达，并诱导细胞周期蛋白E-CDK2激酶活性显著降低。此外，ZNRD1可通过抑制VEGF降低肿瘤微血管密度。综上所述，这些结果表明ZNRD1可能通过靶向细胞周期相关基因和减少肿瘤血管生成来抑制细胞生长。
Previous studies by our laboratory indicated that zinc ribbon domain-containing I (ZNRD1) suppressed the growth of gastric cancer cells with a G, cell cycle arrest. However, the precise molecular mechanism underlying the growth-inhibitory effect of ZNRD1 remained fragmentary. In the present study, we have demonstrated that ZNRD1 could significantly inhibit the in vitro and in vivo growth of gastric cell line MKN28. Human cDNA microarray, reverse transcription-polymerase chain reaction and western blot analyses were used to identify differentially expressed cell cycle-related genes in MKN28 cells over-expressing ZNRD1. ZNRD1-induced growth suppression was found at least partially to regulate various proteins and signaling pathways controlling G, to S progression, including inhibition of cyclin D1 and CDK4, up-regulation of p21(CIP11WAF1) and p27(KiP1) and acceleration of pRb dephosphorylation. Furthermore, ZNRD1 significantly inhibited the transcriptional activity of cyclin D1. p27(Kip1) might play a pivotal role in ZNRD1-induced cell cycle arrest because the P27(Kip1) anti-sense could block the cytostatic effects of ZNRD1. Moreover, ZNRD1 suppressed Skp2 expression via an increase in the protein instability, and induced significant decrease in cyclin E-CDK2 kinase activity. In addition, ZNRD1 could reduce tumor microvessel densities through inhibition of VEGF. Taken together, these results suggested that ZNRD1 might inhibit cell growth by targeting cell cycle-related genes and reducing tumor angiogenesis.