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Carcinogenesis Advance Access originally published online on February 23, 2009
Carcinogenesis 2009 30(4):598-605; doi:10.1093/carcin/bgp047
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

NDRG2 expression decreases with tumor stages and regulates TCF/β-catenin signaling in human colon carcinoma

Young-Jun Kim, Sun Y. Yoon1, Jong-Tae Kim, Eun Y. Song, Hee G. Lee, Hyun J. Son2, Soo Y. Kim3, Daeho Cho1, Inpyo Choi, Joo H. Kim2 and Jae W. Kim*

Stem Cell Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea
1 Department of Biological Sciences, Research Center for Women's disease, Sookmyung Women's University, Hyochangwon-gil 52, Yongsan-gu, Seoul 140-742, Korea
2 Department of Pathology
3 Department of Preventive Medicine, Eulji University School of Medicine, 1306 Dunsan-dong, Seo-gu, Daejeon 302-120, Republic of Korea

* To whom correspondence should be addressed. Tel: +82 42 860 4238; Fax: +82 42 860 4593; Email: wjkim{at}kribb.re.kr

Correspondence may also be addressed to Joo Heon Kim. Tel: +82 42 361 7283; Fax: +82 42 611 3459; Email: kjh2000{at}emc.eulji.ac.kr

NDRG (N-Myc downstream-regulated gene)-2 is a member of the NDRG family. Although it has been suggested that NDRG2 is involved in cellular differentiation and tumor suppression, its intracellular signal and regulatory mechanism are not well known. Here, we show the differential expression of NDRG2 in human colon carcinoma cell lines and tissues by reverse transcription–polymerase chain reaction and immunohistochemical analyses with monoclonal antibody against NDRG2. NDRG2 was strongly expressed in normal colonic mucosa and colonic adenomatous tissues (25 of 25) but not in all invasive cancer tissues [44 of 99 (44%)]. Most distinctive results indicated that the high expression level of NDRG2 has a positive correlation with tumor differentiation and inverse correlation with tumor invasion depth and Dukes’ stage of colon adenocarcinoma. To investigate the roles of NDRG2 in tumorigenesis, we used in vitro cell culture system. SW620 colon cancer cell line with a low level of intrinsic NDRG2 protein was transfected with NDRG2-expressing plasmid. TOPflash luciferase reporter assay showed that the transcriptional activity of T-cell factor (TCF)/lymphoid enhancer factor (LEF) was reduced by NDRG2 introduction, but not by the introduction of mutant NDRG2 generated by deletion or site-directed mutagenesis. Intracellular β-catenin levels were slightly reduced in the NDRG2-transfected SW620 cells and this regulation of β-catenin stability and TCF/LEF activity were mediated through the modulation of glycogen synthase kinase-3beta activity by NDRG2 function. Our results suggest that NDRG2 might play a pivotal role as a potent tumor suppressor by the attenuation of TCF/β-catenin signaling for the maintenance of healthy colon tissues.

Abbreviations: APC, adenomatous polyposis coli; cDNA, complementary DNA; GSK-3β, glycogen synthase kinase-3beta; LEF, lymphoid enhancer factor; MAb, monoclonal antibody; mRNA, messenger RNA; NDRG, N-Myc downstream-regulated gene; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; RT–PCR, reverse transcription–polymerase chain reaction; siRNA, small interfering RNA; TCF, T-cell factor

Received September 15, 2008; revised January 17, 2009; accepted February 14, 2009.


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