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Carcinogenesis Advance Access published online on March 26, 2007
Carcinogenesis, doi:10.1093/carcin/bgm064
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mechanisms of growth arrest by zinc ribbon domain-containing 1 (ZNRD1) in gastric cancer cells

Liu Hong1, Yu Han1, Ying Han1, Yunping Zhao1, Xiaoyin Zhang1, Taidong Qiao1, Zheng Chen1 and Daiming Fan1,2

1 State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China

2 Correspondence should be addressed to D. Fan; E-mail: hlhyhj{at}126.com; Phone: 86-29-84773974; Fax: 86-29-82539041

Previous studies by our laboratory indicated that ZNRD1 suppressed the growth of gastric cancer cells with a G1 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, RT-PCR and western blot analyses were used to identify differentially expressed cell cycle related genes in MKN28 cells overexpressing ZNRD1. ZNRD1-induced growth suppression was found at least partially due to regulate various proteins and signaling pathways controlling G1 to S progression, including inhibition of cyclin D1 and CDK4, up-regulation of p21CIP1/WAF1 and p27Kip1, and acceleration of pRb dephosphorylation. Furthermore, ZNRD1 significantly inhibited the transcriptional activity of cyclin D1. p27Kip1 might play a pivotal role in ZNRD1-induced cell cycle arrest because the p27Kip1 antisense 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.

Key Words: ZNRD1 • zinc ribbon motif • gastric cancer • cell cycle • angiogenesis

Received January 10, 2007; revised February 24, 2007; accepted March 14, 2007.


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