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Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis

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Authors
Lee, Dong Chul; Kang, Yun Kyung; Kim, Woo Ho; Jang, Ye Jin; Kim, Dong Joon; Park, In Young; Sohn, Bo Hwa; Sohn, Hyun Ahm; Lee, Hee Gu; Lim, Jong Seok; Kim, Jae Wha; Song, Eun Young; Kim, Dong Min; Lee, Mi-Ni; Oh, Goo Taeg; Kim, Soo Jung; Park, Kyung Chan; Yoo, Hyang Sook; Choi, Jong Young; Yeom, Young Il
Issue Date
2008
Publisher
American Association for Cancer Research
Citation
Cancer Res 2008;68:4210-20
Keywords
NDRG2; HCC; Metastasis suppressor; ECM; transforming growth factor β
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 beta1-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.
ISSN
0008-5472 (print)1538-7445 (online)
Language
English
URI
http://hdl.handle.net/10371/4602
DOI
https://doi.org/10.1158/0008-5472.CAN-07-5040
https://doi.org/10.1158/0008-5472.CAN-07-5040
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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