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Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis

Title
Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis
Authors
Dong C.L.Yun K.K.Woo H.K.Ye J.J.Dong J.K.In Y.P.Bo H.S.Hyun A.S.Hee G.L.Jong S.L.Jae W.K.Eun Y.S.Dong M.K.Lee M.-N.Goo T.O.Soo J.K.Kyung C.P.Hyang S.Y.Jong Y.C.Young I.Y.
Ewha Authors
오구택이미니
SCOPUS Author ID
오구택scopus; 이미니scopusscopus
Issue Date
2008
Journal Title
Cancer Research
ISSN
0008-5472JCR Link
Citation
vol. 68, no. 11, pp. 4210 - 4220
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA-mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor β1-mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix-based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC. ©2008 American Association for Cancer Research.
DOI
10.1158/0008-5472.CAN-07-5040
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자연과학대학 > 생명과학전공 > Journal papers
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