57447

NDRG2

NDRG family member 2;NDRG2;NDRG family member 2

N-myc downstream regulator 2|N-myc downstream-regulated gene 2 protein|NDR1-related protein NDR2|cytoplasmic protein Ndr1|protein NDRG2|syld709613 protein

14q11.2

protein-coding

N-myc downstream-regulated gene 2 (NDRG2) has been studied for its inhibitory effects against growth and metastasis of many tumor cell types. In this study, we showed NDRG2 expression was correlated with favorable recurrence-free survival of patients with breast cancer and inhibited metastasis of breast cancer cells (4T1). NDRG2 expression was examined in 189 breast carcinoma tissues and paired normal breast tissues using immunohistochemistry. Histological and clinicopathological data were correlated using Pearson's chi-square test of independence. NDRG2 expression in human breast cancer tissues was inversely associated with lymph node metastasis and pTNM stage. Furthermore, patients with breast cancer with a high level of NDRG2 expression showed favorable recurrence-free survival (P = 0.038). To study the effect of NDRG2 on metastasis in vivo, we established an NDRG2-overexpressing mouse breast cancer cell line (4T1-NDRG2) and measured the metastasis and survival of 4T1-NDRG2 tumor-bearing mice. To test whether transforming growth factor beta (TGF-beta)- mediated metastasis of 4T1 was inhibited by NDRG2 expression, TGF-Smad-binding element (SBE)-luciferase activity and/or measurement of active TGF-beta were performed in cell or tumor tissue level. 4T1-NDRG2 cells grew gradually and showed less metastatic activity in vivo and low invasiveness in vitro. 4T1-NDRG2 cells showed lower SBE-luciferase activity and lower level of active autocrine TGF-beta than 4T1-Mock did. Correctly, our data show that NDRG2 significantly suppress tumor metastasis by attenuating active autocrine TGF-beta production, and the attenuation might be typically associated with the favorable recurrence-free survival of patients clinically.

OBJECTIVE: To analyze the expression level of candidate tumor suppressor gene N-Myc downstream-regulated gene 2 (NDRG2) in human colon cancer. METHODS: Thirty samples of colon cancer tissues with matched normal colon tissues were collected. The NDRG2 mRNA level was detected by semi-quantitive RT-PCR and the NDRG2 protein level was examined by Western blot and immunohistochemistry. RESULTS: Twelve samples of colon cancer tissues had low NDRG2 mRNA level and low protein level. The positive rates of NDRG2 in normal tissues and the tumorous colon tissues were 90.0%(27/30) and 53.3%(16/30) by immunohistochemistry respectively. There was a significant difference between two groups (P<0.05). The NDRG2 expression was not correlated with age, sex, metastasis of lymph node, depth of infiltration, as well as the Dukes staging(P>0.05), while it was correlated to the histology grading. The positive rate of NDRG2 in the well- and moderate-differentiation group was higher than that in the poor-differentiation group(P<0.05). CONCLUSION: The expression of NDRG2 is low in some colon cancer tissues, which indicates that the low level of NDRG2 expression may be engaged in the development of colon cancer.

BACKGROUND: Gastric cancer is one of the most common digestive malignancies worldwide. N-myc downstream-regulated gene 2 (NDRG2) is a differentiation-related gene that is considered to be a metastasis suppressor gene. In this study, we examined the expression and DNA methylation of NDRG2 in gastric cancer cell lines and tissues, as well as its clinical significance. METHODS: Six gastric cancer cell lines and 42 paired normal and gastric cancer tissue samples were used to assess NDRG2 mRNA expression using RT-PCR. NDRG2 DNA methylation status was evaluated by methylation-specific PCR (MSP) in gastric cancer cell lines and tissues. The suppression of NDRG2 in BGC823 cells by siRNA transfection was utilized to detect the role of NDRG2 in gastric cancer progression. RESULTS: NDRG2 mRNA was down-regulated in gastric cancer cell lines and tissues, and its expression was just related to lymph node metastasis (p = 0.032). MSP showed methylation of NDRG2 in 54.0 % (47/87) of primary gastric cancer specimens and in 20.0 % (16/80) of corresponding nonmalignant gastric tissues. NDRG2 methylation was related to depth of tumor invasion, Borrmann classification and TNM stage (p < 0.05). Upon treatment with 5-aza-2-deoxycytidine and trichostatin A, NDRG2 expression was upregulated in HGC27 cells, and demethylation of the highly metastatic cell line, MKN45, inhibited cell invasion. Furthermore, the suppression of NDRG2 by siRNA transfection enhanced BGC823 cells invasion. CONCLUSIONS: Our results suggest that the aberrant methylation of NDRG2 may be mainly responsible for its downregulation in gastric cancer, and may play an important role in the metastasis of gastric cancer.

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.

N-myc downstream regulated gene 2 (NDRG2) is involved in invasion and metastasis of cancer, furthermore it is frequently down-regulated in prostate cancer. Herein we evaluated the effect of NDRG2 overexpression on invasiveness and bone destruction in prostate cancer. The human prostate cancer cell line PC-3 and DU145 were infected with Ad-NDRG2 or Ad-LacZ. Overexpression of NDRG2 not only inhibited the growth of the cells, but also suppressed invasiveness of the cells in an in vitro assay. PC-3 cells infected with Ad-NDRG2 or Ad-LacZ were injected into the tibias of nude mice. Four weeks later, we found the mice injected with PC-3 cells overexpressing NDRG2 had smaller tumors and less bone destruction. These results demonstrate that NDRG2 overexpression can inhibit tumor growth and invasion, furthermore, it can decrease bone destruction caused by prostate cancer bone metastasis.