Abstract
The N-myc downstream-regulated gene-1 (NDRG1) has recently been proposed as a metastasis suppressor, but its precise role remains unclear. To investigate whether NDRG1 can indeed influence the metastasis progress, expression of endogenous NDRG1 was knocked down in human AGS gastric adenocarcinoma cells using RNA interference. Stable NDRG1 “silenced” transfectants showed similar growth rates as their control counterparts. By contrast, invasive ability in Matrigel invasion activity and Gelatinolytic activity by matrix metalloproteinase-2 (MMP-2) were markedly increased in NDRG1 “silenced” cells. Moreover, re-expression of NDRG1 by recombinant adenovirus Ad-NDRG1 in NDRG1 “silenced” cells inhibited the increased invasive ability. Further study, we found the induction of MMP-2 by downregulation of NDRG1 was mediated by MT1-MMP. Altogether, our results imply that NDRG-1 could play a key role in the regulation of cellular invasion and metastasis, which may involve the upregulation of matrix metalloproteinases.
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References
Arkenau HT. Gastric cancer in the era of molecularly targeted agents: current drug development strategies. J Cancer Res Clin Oncol. 2009;135:855–66.
Kountouras J, Zavos C, Chatzopoulos D, Katsinelos P. New aspects of Helicobacter pylori infection involvement in gastric oncogenesis. J Surg Res. 2008;146:149–58.
Iiizumi M, Liu W, Pai SK, Furuta E, Watabe K. Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy. Biochim Biophys Acta. 2008;1786:87–104.
Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006;27:2355–66.
Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res. 1998;58:4439–44.
Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 2000;60:749–55.
Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, et al. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene. 2004;23:5675–81.
Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, et al. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 2003;63:1731–6.
Agarwala KL, Kokame K, Kato H, Miyata T. Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein. Biochem Biophys Res Commun. 2000;272:641–7.
Cangul H, Salnikow K, Yee H, Zagzag D, Commes T, Costa M. Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect. 2002;110 Suppl 5:783–8.
Shin MH, Lee EG, Lee SH, Lee YS, Son H. Neural cell adhesion molecule (NCAM) promotes the differentiation of hippocampal precursor cells to a neuronal lineage, especially to a glutamatergic neural cell type. Exp Mol Med. 2002;34:401–10.
Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson II RS, et al. NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem. 2004;279:48930–40.
Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, et al. Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res. 2006;66:6233–42.
Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta. 2005;1755:37–69.
Noel A, Jost M, Maquoi E. Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol. 2008;19:52–60.
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994;370:61–5.
Inagaki Y, Tang W, Xu HL, Guo Q, Mafune K, Konishi T, et al. Localization of N-myc downstream-regulated gene 1 in gastric cancer tissue. Dig Liver Dis. 2009;41:96–103.
Lunt SJ, Chaudary N, Hill RP. The tumor microenvironment and metastatic disease. Clin Exp Metastasis. 2009;26:19–34.
Mori M, Mimori K, Shiraishi T, Fujie T, Baba K, Kusumoto H, et al. Analysis of MT1-MMP and MMP2 expression in human gastric cancers. Int J Cancer. 1997;74:316–21.
Alakus H, Grass G, Hennecken JK, Bollschweiler E, Schulte C, Drebber U, et al. Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer. Histol Histopathol. 2008;23:917–23.
Bae IH, Park MJ, Yoon SH, Kang SW, Lee SS, Choi KM, et al. Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1. Cancer Res. 2006;66:4991–5.
Acknowledgments
This study was supported by the grants NSFC (Natural Science Foundation of China) no. 30670100 and also partially supported by the grants Scientific Research Plan funded by Shaanxi Provincial Department of Education no.07JK371. The authors deeply thank Dr. Costa M (Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY) for providing the NDRG1 cDNA expression plasmid. We thank the anonymous reviewers for their insightful comments.
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Yan-li Liu and Wen-tao Bai contributed equally to this work.
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Liu, Yl., Bai, Wt., Luo, W. et al. Downregulation of NDRG1 promotes invasion of human gastric cancer AGS cells through MMP-2. Tumor Biol. 32, 99–105 (2011). https://doi.org/10.1007/s13277-010-0103-z
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DOI: https://doi.org/10.1007/s13277-010-0103-z