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

Chul Lee Dong, Kyung Kang Yun, Ho Kim Woo, Jin Jang Ye, Joon Kim Dong, Young Park In, Hwa Sohn Bo, Ahm Sohn Hyun, Gu Lee Hee, Seok Lim Jong, Wha Kim Jae, Young Song Eun, Min Kim Dong, Mi Ni Lee, Taeg Oh Goo, Soo Jung Kim, Chan Park Kyung, Sook Yoo Hyang, Young Choi Jong, Il Yeom Young

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4210-4220
Number of pages11
JournalCancer Research
Volume68
Issue number11
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

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Liver Neoplasms
Neoplasm Metastasis
Hepatocellular Carcinoma
Genes
Neoplasms
Gene Expression
Cell Line
rho GTP-Binding Proteins
Matrix Metalloproteinase 2
Transforming Growth Factors
Portal Vein
Tumor Cell Line
Genetic Promoter Regions
Small Interfering RNA
Cell Movement
Extracellular Matrix
Proteins
Thrombosis
Survival Rate
RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dong, C. L., Yun, K. K., Woo, H. K., Ye, J. J., Dong, J. K., In, Y. P., ... Young, I. Y. (2008). Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis. Cancer Research, 68(11), 4210-4220. https://doi.org/10.1158/0008-5472.CAN-07-5040

Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis. / Dong, Chul Lee; Yun, Kyung Kang; Woo, Ho Kim; Ye, Jin Jang; Dong, Joon Kim; In, Young Park; Bo, Hwa Sohn; Hyun, Ahm Sohn; Hee, Gu Lee; Jong, Seok Lim; Jae, Wha Kim; Eun, Young Song; Dong, Min Kim; Lee, Mi Ni; Goo, Taeg Oh; Kim, Soo Jung; Kyung, Chan Park; Hyang, Sook Yoo; Jong, Young Choi; Young, Il Yeom.

In: Cancer Research, Vol. 68, No. 11, 01.06.2008, p. 4210-4220.

Research output: Contribution to journalArticle

Dong, CL, Yun, KK, Woo, HK, Ye, JJ, Dong, JK, In, YP, Bo, HS, Hyun, AS, Hee, GL, Jong, SL, Jae, WK, Eun, YS, Dong, MK, Lee, MN, Goo, TO, Kim, SJ, Kyung, CP, Hyang, SY, Jong, YC & Young, IY 2008, 'Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis', Cancer Research, vol. 68, no. 11, pp. 4210-4220. https://doi.org/10.1158/0008-5472.CAN-07-5040
Dong, Chul Lee ; Yun, Kyung Kang ; Woo, Ho Kim ; Ye, Jin Jang ; Dong, Joon Kim ; In, Young Park ; Bo, Hwa Sohn ; Hyun, Ahm Sohn ; Hee, Gu Lee ; Jong, Seok Lim ; Jae, Wha Kim ; Eun, Young Song ; Dong, Min Kim ; Lee, Mi Ni ; Goo, Taeg Oh ; Kim, Soo Jung ; Kyung, Chan Park ; Hyang, Sook Yoo ; Jong, Young Choi ; Young, Il Yeom. / Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis. In: Cancer Research. 2008 ; Vol. 68, No. 11. pp. 4210-4220.
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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.",
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