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

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 B1-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.

NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer

“…15 Previous studies from our group and others have demonstrated that NDRG2 is involved in cell differentiation, 17 proliferation, 18 apoptosis 19,20 and the stress response. 21 NDRG2 in particular has been proposed as a tumor suppressor 21 because mounting evidence demonstrates that NDRG2 is deregulated in various carcinomas, including glioblastoma, 15 breast cancer, 22 hepatocellular cancer 23 and colorectal cancer, 24 while upregulating NDRG2 could reverse the malignant phenotype of cancer cells. 21,25,26 Our most recent studies showed that NDRG2 expression levels were lower in PC tissues than in their benign counterparts, and forced expression of NDRG2 inhibited the proliferation and invasion of PC cells.…”

Genomic Profiling of MicroRNAs and Proteomics Reveals an Early Molecular Alteration Associated with Tumorigenesis Induced by MC-LR in Mice

“…42 NDRG2 was considered as a new tumor suppressor gene candidate. 43 Lee et al 44 found that the expression of NDRG2 was significantly reduced in HCC and suggested that NDRG2 could suppress tumor cell invasion and migration. Regucalcin (RGN), a novel Ca 2+ -binding protein, has been shown to play a multifunctional role as a regulatory protein.…”

Overexpression of NDRG2 Can Inhibit Neuroblastoma Cell Proliferation through Negative Regulation by CYR61

“…In several studies, low-expression of NDRG2 was found in multiple types of cancers or cells (Lusis et al, 2005;Lorentzen et al, 2007;Lee et al, 2008;Zhao et al, 2008;Shi et al, 2009). For example, NDRG2 was highly expressed in normal colonic mucosa and colonic adenomatous tissues, but was expressed at lower levels in all invasive cancer tissues .…”