Carcinogenesis Advance Access originally published online on March 31, 2009
Carcinogenesis 2009 30(6):927-936; doi:10.1093/carcin/bgp072
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Suppression of NF-
B activity by NDRG2 expression attenuates the invasive potential of highly malignant tumor cells
Department of Biological Science and Research Center for Women's Diseases, Sookmyung Women's University, Chungpa-Dong, Yongsan-Gu, Seoul 140-742, Republic of Korea
1 Stem Cell Center
2 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea
* To whom correspondence should be addressed. Tel: +82 2 710 9560; Fax: +82 2 2077 7322; Email: jslim{at}sookmyung.ac.kr
Downregulation of the N-myc downstream-regulated gene 2 (NDRG2) gene is involved in the progression of aggressive forms of cancer, along with the poor prognosis of cancer patients. In the current study, we examined the effect of NDRG2 expression on the metastatic potential of HT1080 human fibrosarcoma and B16F10 murine melanoma cells in both in vitro and in vivo systems. In gelatin zymography, NDRG2 expression remarkably suppressed the matrix metalloproteinase (MMP)-9 activity and slightly inhibited MMP-2 activity of both cell lines. Tumor migration and invasion in vitro were significantly reduced by NDRG2 expression, and NDRG2 inhibited tumor cell proliferation in an anchorage-independent semisolid agar assay. Specifically, we found that NDRG2 affects invasion through suppression of nuclear factor kappa B (NF-
B) activity. In animal experiments, subcutaneously injected B16F10-NDRG2 cells showed delayed tumor growth compared with B16F10-mock cells. Furthermore, severe metastasis from primary tumor mass into the draining lymph nodes was observed after injection of B16F10-mock cells, but not with B16F10-NDRG2 cells. Pulmonary metastasis after intravenous injection of B16F10 cells was also reduced by NDRG2 expression. Intra- and peritumoral angiogenesis that is critical for the tumor growth and metastasis was clearly found in tumors after injection with B16F10-mock cells, whereas it was impaired in tumors after injection with B16F10-NDRG2 cells. Collectively, our data show that NDRG2 expression significantly suppresses tumor invasion by inhibiting MMP activities, which are regulated through the NF-B signaling. Moreover, results from animal experiments provide evidence for the regulatory role of the NDRG2 gene in metastatic tumors.
Abbreviations: AM, acetomethylester; AP-1, activator protein-1; CM, conditioned medium; DMEM, Dulbecco's modified Eagle's medium; ECM, extracellular matrix; FBS, fetal bovine serum; IKK, IB kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; NDRG2, N-myc downstream-regulated gene 2; NF-B, nuclear factor kappa B; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PECAM-1, platelet-endothelial cell adhesion molecule-1; PMA, phorbol-12-myristate-13-acetate; s.c., subcutaneously; siRNA, small interfering RNA; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor
Received November 22, 2008; revised February 28, 2009; accepted March 20, 2009.
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