57447

NDRG2

SYLD;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

Although meningiomas are common central nervous system tumors, little is known about the genetic events responsible for malignant progression. In this study, we employed gene expression profiling to identify transcripts whose expression was lost in anaplastic (WHO grade III) versus benign (WHO grade I) meningioma. Approximately 40% of genes down-regulated in anaplastic meningioma were localized to chromosomes 1p and 14q. One specific gene located at 14q11.2, NDRG2, was consistently down-regulated in grade III meningioma, a finding which we validated at both the transcript and protein levels in independent sets of clinically and pathologically diverse meningiomas. Loss of NDRG2 expression was also seen in a subset of lower-grade meningiomas, including atypical meningiomas (WHO grade II) with clinically aggressive behavior. Furthermore, we found that the loss of NDRG2 expression was significantly associated with hypermethylation of the NDRG2 promoter. Collectively, these data identify NDRG2 as the first specific candidate tumor suppressor gene on chromosome 14q that is inactivated during meningioma progression. In addition, these findings highlight the utility of combining genomic, epigenetic, and expression data to identify clinically significant tumor biomarkers, and suggest that NDRG2 expression will be a useful and functionally relevant biomarker to predict aggressive behavior in patients with meningioma.

Clear cell renal cell carcinoma (CCRCC) is the most common pathological type of renal cell carcinoma and the main cause of renal carcinoma mortality. NDRG2, a new member of the N-Myc downstream-regulated gene (NDRG) family, is a focus for study at present. Up to now, its expression and function in carcinoma remain unclear. The aim of this study was to investigate its expression in CCRCC tissues and several renal carcinoma cell lines. The expression of NDRG2 was evaluated in renal cell carcinoma cell lines, tumor and adjacent non-tumor tissues from same clear cell renal cell carcinoma patients, by using immunohistochemistry, immunofluorescence, RT-PCR and Western blot. By immunohistochemistry and immunofluorescence we found that NDRG2 was predominantly located in the cytoplasm and membrane of renal carcinoma cancer cells, and the positive rate of NDRG2 in renal carcinoma specimens was 30.3% (40/132), which is significantly lower than 91.67% (121/132) in normal renal tissues (p<0.01). The average staining score in normal renal tissues was significantly higher than renal carcinoma (6.12+/-1.84 versus 2.65+/-1.23, p<0.01). Moreover, NDRG2 mRNA and protein were down-regulated in 6 fresh CCRCC tissues compared with their adjacent noncancerous tissues and normal tissues. Its expression was also lower in the human CCRCC-derived cell lines A-498 and 786-O than in the human proximal tubular cell lines HK-2 and HKC. These results indicated that NDRG2 might play an important role in the carcinogenesis and development of CCRCC and may function as a tumor suppressor in CCRCC.

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.

The N-myc downstream-regulated gene 2 (NDRG2) at 14q11.2 has been reported to be downregulated in glioblastoma, and NDRG2 overexpression represses glioblastoma cell proliferation in vitro (Deng et al., Int J cancer 2003;106;342-7). To further address the role of NDRG2 as a candidate tumor suppressor in human gliomas, we analyzed 67 astrocytic tumors (10 diffuse astrocytomas, 11 anaplastic astrocytomas, 34 primary glioblastomas and 12 secondary glioblastomas) for NDRG2 gene mutation, promoter methylation and expression at the mRNA and protein levels. Using real-time reverse transcription PCR analysis, we found decreased NDRG2 mRNA levels in primary glioblastomas as compared to diffuse and anaplastic astrocytomas. Similarly, immunohistochemistry revealed low or absent NDRG2 protein expression in primary glioblastomas. mutational analysis of the entire NDRG2 coding sequence did not reveal any tumor-associated DNA sequence alterations. However, sequencing of sodium bisulfite-modified DNA identified hypermethylation of the NDRG2 promoter region in 21 of 34 primary glioblastomas (62%). Moreover, NDRG2 promoter hypermethylation was associated with decreased NDRG2 mRNA expression. In contrast to primary glioblastomas, NDRG2 promoter hypermethylation was detected in only 1 of 11 anaplastic astrocytomas (9%) and was absent in 10 diffuse astrocytomas and 12 secondary glioblastomas. Taken together, our data support NDRG2 as a candidate tumor suppressor gene that is epigenetically silenced in the majority of primary glioblastomas, but not in lower grade astrocytomas and secondary glioblastomas.

OBJECTIVE: To determine the expression of new candidate tumor suppressor gene N-Myc downstream-regulated gene 2(Ndrg2) in colorectal cancer with different differentiation, and analyze its clinical significance. METHODS: Specimens of 50 colorectal cancer patients with different differentiation were collected. Immunohistochemistry and Western blot were used to examine the expression of Ndrg2. Colorectal cancer tissue array in large scale was applied to analyze the expression of Ndrg2 and the statistics analysis was performed referring to the patients information of the array. RESULTS: Among 50 cases, Ndrg2 expression level of colorectal cancer was significantly lower in 32 cases as compared to adjacent and normal tissue of the same individual, while Ndrg2 expression of adjacent tissue was significantly lower than that of normal tissue. Ndrg2 protein levels increased from poor-differentiated to well-differentiated carcinomas(P=0.005). CONCLUSIONS: The expression of Ndrg2 in different differentiated colorectal cancer tissues show a significant distinction. Ndrg2 may be involved in the regulation of differentiation in colorectal cancer.

Oral cancer is one of the most common cancers worldwide, and squamous-cell carcinoma (OSCC) is the most common phenotype of oral cancer. Although patients with OSCC have poor survival rates and a high incidence of metastasis, the molecular mechanisms of OSCC development have not yet been elucidated. This study investigated whether N-myc downstream-regulated gene 2 (NDRG2) contributes to the carcinogenesis of OSCC, as NDRG2 is reported to be a candidate tumor-suppressor gene in a wide variety of cancers. The down-regulation of NDRG2 mRNA, which was dependent on promoter methylation, was seen in the majority of OSCC cases and in several cases of precancerous leukoplakia with dysplasia. Induction of NDRG2 expression in an HSC-3/OSCC cell line significantly inhibited cell proliferation and decreased colony formation ability on soft agar. The majority of OSCC cell lines showed an activation of PI3K/Akt signaling, and enforced expression of NDRG2 in HSC-3 cells decreased the level of phosphorylated Akt at Serine 473 (p-Akt). Immunohistochemical p-Akt staining was detected in 56.5% of the OSCC tumors, and 80.4% of the tumors were negative for NDRG2 staining. Moreover, positive p-Akt staining was inversely correlated with decreased NDRG2 expression in OSCC tumors with moderate to poor differentiation (p<0.005). Therefore, NDRG2 is a candidate tumor-suppressor gene for OSCC development and probably contributes to the tumorigenesis of OSCC partly via the modulation of Akt signaling.

Considerable attention has recently been paid to the N-Myc downstream-regulated gene (NDRG) family because of its potential as a tumor suppressor in many human cancers. Primary amino acid sequence information suggests that the NDRG family proteins may belong to the alpha/beta-hydrolase (ABH) superfamily; however, their functional role has not yet been determined. Here, we present the crystal structures of the human and mouse NDRG2 proteins determined at 2.0 and 1.7 A resolution, respectively. Both NDRG2 proteins show remarkable structural similarity to the ABH superfamily, despite limited sequence similarity. Structural analysis suggests that NDRG2 is a nonenzymatic member of the ABH superfamily, because it lacks the catalytic signature residues and has an occluded substrate-binding site. Several conserved structural features suggest NDRG may be involved in molecular interactions. Mutagenesis data based on the structural analysis support a crucial role for helix alpha6 in the suppression of TCF/beta-catenin signaling in the tumorigenesis of human colorectal cancer, via a molecular interaction.