Carcinogenesis Advance Access published online on February 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp047
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NDRG2 expression decreases with tumor stages and regulates TCF/β-catenin signaling in human colon carcinoma
1 Stem Cell Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333
2 Department of Biological Sciences, Research Center for Women's disease, Sookmyung Women's University, Hyochangwon-gil 52, Yongsan-gu, Seoul 140-742
3 Department of Pathology
4 Department of Preventive Medicine, Eulji University School of Medicine, 1306 Dunsan-dong, Seo-gu, Daejeon 302-120, Republic of Korea
Address for Correspondence: Jae Wha Kim, Ph.D., Stem Cell Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea. Tel: 42-860-4238, Fax: 42-860-4593, E-mail: wjkim{at}kribb.re.kr or Joo Heon Kim, MD., Department of Pathology, Eulji University School of Medicine, Daejeon, Republic of Korea. Tel: 42-361-7283, E-mail: kjh2000{at}emc.eulji.ac.kr
NDRG2 is a member of the N-Myc downstream-regulated gene 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 RT-PCR and immunohistochemical analyses with monoclonal antibody (mAb) 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 TCF/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 GSK-3β 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.
Key Words: N-Myc downstream-regulated gene 2 (NDRG2) • T-cell factor (TCF)/Lymphoid enhancer factor (LEF) • β-catenin signaling
Received September 15, 2008; revised January 17, 2009; accepted February 14, 2009.
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