Gene Summary

Gene:NDRG2; NDRG family member 2
Aliases: SYLD
Summary:This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that may play a role in neurite outgrowth. This gene may be involved in glioblastoma carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein NDRG2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: NDRG2 (cancer-related)

Tsui KH, Hou CP, Chang KS, et al.
Metallothionein 3 Is a Hypoxia-Upregulated Oncogene Enhancing Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (

Yang YQ, Tian T, Zhu HY, et al.
NDRG2 mRNA levels and miR-28-5p and miR-650 activity in chronic lymphocytic leukemia.
BMC Cancer. 2018; 18(1):1009 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NDRG2 is identified as a tumor suppressor gene in many tumors, and functions in cell proliferation, differentiation and apoptosis. Recent data indicate that NDRG2 expression is up-regulated by TP53. Moreover, proposed mechanisms of NDRG2 inactivation include epigenetic silencing of the NDRG2 promoter and down-regulation by microRNAs (miRNAs). However, few studies have ever been done on the role of NDRG2 and the NDRG2-regulating miRNAs interference in chronic lymphocytic leukemia (CLL).
METHODS: NDRG2 and microRNAs mRNA levels in CLL subjects were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was performed to determine NDRG2-related miRNAs. Low expression of mature exogenous miRNAs in CLL cells was established by transient transfection. NDRG2 protein levels in CLL cells were detected by western blot. In addition, flow cytometry was conducted to examine the apoptosis of CLL cells.
RESULTS: Lower expression of NDRG2 was found in the B-cells from 102 CLL patients compared the 40 normal subjects (P < 0.001). Patients with advanced Binet stage (P = 0.001), high lactate dehydrogenase (LDH) level (P = 0.036), un-mutated immunoglobulin heavy chain variable region gene (IGHV) (P = 0.004) and those with p53 aberrations (P < 0.001) had a markedly lower levels of NDRG2 mRNA. This decrease was associated with briefer time-to-treatment (P = 0.001) and poorer survival (P < 0.001). High expression of miR-28-5p and miR-650 was associated with Binet B/C stage (P = 0.044) and IGHV un-mutated (P = 0.011), as well as Binet B/C stage (P = 0.013) and p53 aberrations (P = 0.037), respectively. Inhibition of miR-28-5p or miR-650 could induce more apoptosis in CLL cells with germline TP53.
CONCLUSIONS: NDRG2 mRNA levels might be a useful prognostic variable for patients of CLL and up-regulating NDRG2 transcription may be a therapy approach in CLL without p53 aberrations.

Vaes N, Schonkeren SL, Brosens E, et al.
A combined literature and in silico analysis enlightens the role of the NDRG family in the gut.
Biochim Biophys Acta Gen Subj. 2018; 1862(10):2140-2151 [PubMed] Related Publications
BACKGROUND: The N-Myc Downstream-Regulated Gene (NDRG) family comprises four members that function in cellular processes like proliferation and differentiation. While NDRG1 and NDRG2 are extensively studied, knowledge regarding NDRG3 and NDRG4, despite its recognition as a well-established early-detection marker for colorectal cancer (Cologuard®), is sparse.
SCOPE OF REVIEW: To summarize expression, biomarker potential and functional mechanisms of the NDRGs in the developing, mature and cancerous gut, we combine current literature and in silico analyses from the TCGA-database, GTEX Project, E14.5 mouse intestine and enteric neural crest cells, and an RNA-sequencing time-series of human embryonic colonic samples.
MAJOR CONCLUSIONS: This study reveals that all members display a differential expression pattern in the gut and that NDRG1, NDRG2 and NDRG4 (1) can serve as biomarker for colorectal cancer and (2) have tumor suppressive properties mainly affecting cell proliferation and epithelial-mesenchymal transition.
GENERAL SIGNIFICANCE: Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

Yang CL, Zheng XL, Ye K, et al.
NDRG2 suppresses proliferation, migration, invasion and epithelial-mesenchymal transition of esophageal cancer cells through regulating the AKT/XIAP signaling pathway.
Int J Biochem Cell Biol. 2018; 99:43-51 [PubMed] Related Publications
N-Myc downstream-regulated gene 2 (NDRG2) has recently revealed as a candidate tumor suppressor gene. To inhibit tumor growth and decrease morbidity of esophageal cancer (EC), this study aims to test the hypothesis that the upregulation of NDRG2 may suppress proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of EC cells by regulating the AKT/XIAP signaling pathway. Immunohistochemistry was conducted for the identification of NDRG2, protein kinase B (p-AKT), X-linked inhibitor of apoptosis protein (XIAP) in EC tissues. To identify the regulatory mechanism of NDRG2 on the AKT/XIAP signaling pathway and EMT in EC, over-expressed lentiviral vector and shRNA were applied for up-regulating and interfering NDRG2 expression, and a series of determinations on the biological behavior of EC cells were performed to validate this regulation action. The results of immunohistochemistry showed NDRG2 was lowly expressed in EC tissues while p-AKT and XIAP are highly expressed. Over-expression of NDRG2 suppresses the proteins related to AKT/XIAP signaling pathway and EMT. Besides, a series of determinations shows the proliferation, migration and invasion of TE-13 cells were suppressed by over-expressed NDRG2, while the cell cycle progression was blocked and cell apoptosis was promoted. And in vivo experiment also demonstrated NDRG2 could inhibit tumor growth. Our findings demonstrate over-expression of NDRG2 works as tumor suppressive role in EC through its effects on inhibition of cell migration, invasion, and EMT by inhibiting the AKT/XIAP signaling pathway.

Agosta C, Laugier J, Guyon L, et al.
MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer.
Int J Cancer. 2018; 143(4):944-957 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-myc downstream-regulated gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage-independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies.

Shen L, Qu X, Li H, et al.
NDRG2 facilitates colorectal cancer differentiation through the regulation of Skp2-p21/p27 axis.
Oncogene. 2018; 37(13):1759-1774 [PubMed] Free Access to Full Article Related Publications
Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses β-catenin nuclear translocation and decreases the occupancy of β-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3β. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH

Chen XL, Lei L, Hong LL, Ling ZQ
Potential role of NDRG2 in reprogramming cancer metabolism and epithelial-to-mesenchymal transition.
Histol Histopathol. 2018; 33(7):655-663 [PubMed] Related Publications
Epithelial-to-mesenchymal transition (EMT) allows a cell with epithelial characteristics to transdifferentiate into a cell with mesenchymal characteristics, which is recognized as a key priming event for the initiation and evolvement of cancer metastasis. Accumulating data have shown that aberrant cancer metabolism contributes to the execution of EMT and cancer metastasis through multiple pathological pathways. Recently, the N-MYC downstream-regulated gene 2 (NDRG2), as a tumor suppressor and metabolism-related gene in various cancers, has been widely noted. NDGR2 is associated with energy metabolism, especially glycose metabolism. Hence, we propose a hypothesis that EMT is repressed by NDRG2 via cancer metabolic reprogramming, and summarize the pathological processes and molecular pathways related to the regulation of NDRG2.

He P, Yang JW, Yang VW, Bialkowska AB
Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice.
Gastroenterology. 2018; 154(5):1494-1508.e13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Krüppel-like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs.
METHODS: We performed studies in adult mice with conditional disruption of Klf5 (Klf5
RESULTS: Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-Cre
CONCLUSION: Levels of KLF5 are increased in human PDAC samples and in PanINs of Ptf1a-Cre

Fu Q, Gao Y, Yang F, et al.
Suppression of microRNA-454 impedes the proliferation and invasion of prostate cancer cells by promoting N-myc downstream-regulated gene 2 and inhibiting WNT/β-catenin signaling.
Biomed Pharmacother. 2018; 97:120-127 [PubMed] Related Publications
MicroRNA-454 (miR-454) is emerging as critical regulator in tumorigenesis; it may function as an oncogene or a tumor suppressor. However, the role of miR-454 in prostate cancer remains unknown. In this study, we aimed to investigate the function and molecular mechanisms of miR-454 in prostate cancer. We found that miR-454 was highly expressed in prostate cancer tissues and cell lines (*p<0.05), as detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 assay, colony formation assay and cell invasion assay showed that the inhibition of miR-454 significantly suppressed prostate cancer cell proliferation and invasion (*p<0.05), whereas the overexpression of miR-454 markedly promoted prostate cancer cell proliferation and invasion (*p<0.05). Bioinformatics analysis showed that N-myc downstream-regulated gene 2 (NDRG2), a well-known tumor suppressor, was identified as a potential target gene of miR-454. Dual-luciferase reporter assay showed that miR-454 directly targeted the 3'-untranslated region of NDRG2. RT-qPCR and western blot showed that miR-454 overexpression significantly decreased NDRG2 expression (*p<0.05), whereas miR-454 inhibition markedly promoted NDRG2 expression (*p<0.05). Spearman's correlation analysis showed that miR-454 expression was inversely correlated with NDRG2 expression in prostate cancer tissues (r=-0.8932; p<0.0001). Moreover, miR-454 inhibition significantly suppressed the protein expression of β-catenin (*p<0.05) and blocked the activation of WNT signaling (*p<0.05). In addition, small interfering RNA mediated NDRG2 knockdown significantly reversed the antitumor effect of miR-454 inhibition on prostate cancer cell proliferation and invasion (*p<0.05). Taken together, these results reveal an oncogenic role of miR-454, which promotes prostate cancer cell proliferation and invasion by downregulation of NDRG2. These results also suggest miR-454 as a potential therapeutic target for the treatment of prostate cancer.

Hu XY, Liu Z, Zhang KL, et al.
SUMO-specific protease 2-mediated deSUMOylation is required for NDRG2 stabilization in gastric cancer cells.
Cancer Biomark. 2017; 21(1):195-201 [PubMed] Related Publications
N-myc downstream regulated gene 2 (NDRG2) is frequently down-regulated in various cancers and functions as a candidate tumor suppressor gene. NDRG2 has been shown to be SUMOylated on the lysine 333 residue, which promoted its ubiquitination and sequentially degradation by the SUMO-targeted ubiquitin E3 ligase RNF4. However, how to regulated NDRG2 deSUMOylation process remains largely unknown. Here, we report that Sentrin/SUMO specific protease (SENP2) was down-regulated in clinic gastric cancer samples and possessed a tumor-suppressive role in gastric cancer. At the molecular level, we found that SENP2 interacts with NDRG2 and mediates the de-SUMOylation process of NDRG2. Overexpression of SENP2 stabilized NDRG2, whereas silencing SENP2 caused rapid NDRG2 SUMOylation and degradation, indicating SENP2 antagonizes NDRG2 ubiquitination and degradation, thereby promoting the stability and function of this protein. Thus, our study reveals that SENP2 acts as a tumor suppressor which is deregulated in gastric cancer and the specific de-SUMOylation activity of SENP2 for NDRG2 is critical for it stabilization as well as gastric cancer cells proliferation.

Zhang M, Ren B, Li Z, et al.
Expression of N-Myc Downstream-Regulated Gene 2 in Bladder Cancer and Its Potential Utility as a Urinary Diagnostic Biomarker.
Med Sci Monit. 2017; 23:4644-4649 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Initial diagnosis of carcinoma of the urinary bladder remains challenging. N-Myc downstream-regulated gene 2 (NDRG2) has been reported to be closely correlated with cell differentiation and proliferation in various cancers. However, its clinical significance in diagnosis of bladder cancer remains unclear. The purpose of this study was to detect the expression of NDRG2 and investigate its diagnostic value in bladder cancer. MATERIAL AND METHODS We recruited 127 patients with bladder cancer and 97 healthy controls. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting analysis were conducted to measure the NDRG2 expression levels in urine of patients with bladder cancer, bladder cancer cell lines, and healthy controls. The correlations between NDRG2 expression and clinicopathological characteristics were analyzed by chi-square test, and the diagnostic value of NDRG2 was estimated by establishing a receiver operating characteristic (ROC) curve. RESULTS The relative NDRG2 expression were significantly downregulated both at mRNA and protein levels in urine of patients with bladder cancer and in cell lines, and its low expression was distinctively correlated with tumor grade and stage. The ROC curve showed NDRG2 could be a good diagnostic marker, with an AUC of 0.888, indicating high sensitivity and specificity. CONCLUSIONS NDRG2 was decreased in patients with bladder cancer and might be involved in the progression of this malignancy. Moreover, NDRG2 could be a potential independent diagnostic biomarker for bladder cancer.

Ma Y, Wu L, Liu X, et al.
KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling.
Oncol Rep. 2017; 38(2):975-984 [PubMed] Related Publications
Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor, which was confirmed as a tumor suppressor gene in colorectal cancers. KLF4 inhibits colorectal cancer cells proliferation through upregulating p21WAF1/Cip1 and downregulating cyclin D1. We firstly reported that N-Myc downstream regulated gene 2 (NDRG2) was a novel tumor suppressor gene in multiple cancers, such as glioma, breast cancer and colorectal cancer. Herein, we provide novel evidence that KLF4 can transcriptionally activate NDRG2 by binding with NDRG2 promoter. With MTT assay, EdU staining, colony formation assay and xenograft mouse model, we confirmed that KLF4 inhibited colorectal cancer cell proliferation and tumorigenesis dependent on NDRG2. Finally, with tissue array analysis, we found a positive correlation of combined detection of KLF4/NDRG2 co-expression with TNM grades and differentiation levels of colorectal cancer. Lower expression of KLF4 and NDRG2 in colorectal cancer patients was correlated with poor overall survival. Thus, KLF4 inhibited the proliferation of colorectal cancer cells dependent on NDRG2 signaling, which provides a novel strategy for therapy and early diagnosis of colorectal cancer.

Wei Y, Yu S, Zhang Y, et al.
NDRG2 promotes adriamycin sensitivity through a Bad/p53 complex at the mitochondria in breast cancer.
Oncotarget. 2017; 8(17):29038-29047 [PubMed] Free Access to Full Article Related Publications
Chemo-resistance presents a difficult challenge for the treatment of breast cancer. Our previous study showed that N-Myc downstream-regulated gene 2 (NDRG2) is involved in p53-mediated apoptosis induced by chemotherapy, through a mechanism that has so far remained obscure. Here, we explored the role of NDRG2 in chemo-resistance with a focus on Adriamycin (ADR) and found that NDRG2 expression decreased in ADR resistance breast cancer cells. Interestingly, NDRG2 can promote ADR sensitivity by inhibiting proliferation, enhancing cellular damage responses, and promoting apoptosis in a p53-dependent manner. We also found that NDRG2 could upregulate Bad expression by increasing its half-life, which is associated with p53 to mitochondria. Hence, our collective data provided the first evidence that NDRG2 promoting sensitivity of breast cancer is dependent on p53 by preventing p53 from entering the nucleus rather than changing its expression.

Vaitkiene P, Valiulyte I, Glebauskiene B, Liutkeviciene R
N-myc downstream-regulated gene 2 (NDRG2) promoter methylation and expression in pituitary adenoma.
Diagn Pathol. 2017; 12(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pituitary adenoma (PA) is a benign primary tumor that arises from the pituitary gland and is associated with ophthalmological, neurological and endocrinological abnormalities. However, causes that increase tumor progressing recurrence and invasiveness are still undetermined. Several studies have shown N-myc downstream regulated gene 2 (NDRG2) as a tumor suppressor gene, but the role of NDRG2 gene in pituitary adenoma pathogenesis has not been elucidated. The aim of our research has been to examine NDRG2 mRNA expression in PA and to determine the associations between the NDRG2 gene epigenetic changes and the development of recurrence or invasiveness of PA and patient clinical data.
METHODS: The MS-PCR was used for NDRG2 promoter methylation analysis and gene mRNA expression levels were evaluated by qRT-PCR in 68 non-functioning and 73 functioning adenomas. Invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Statistical analysis was performed to find correlations between NDRG2 gene mRNA expression, promoter methylation and patient clinical characteristics and PA activity.
RESULTS: The NDRG2 mRNA expression was significantly lower in the case of acromegaly (GH and IGF-1 hypersecretion) than in other diagnoses of PAs (p < 0.05). Also, the NDRG2 expression was significantly higher in prolactinoma (PRL hypersecretion) than in in other diagnoses of PAs (p < 0.05). The promoter of NDRG2 was methylated in 22.69% (12/58 functioning and 15/61 non-functioning) of patients with PA. However, the NDRG2 gene mRNA expression was not significantly related to its methylation status. Clinical factors, such as: age, gender, relapse and diagnoses of Cushing syndrome were of no significance for NDRG2 promoter methylation and mRNA expression levels, as well as secreting or non-secreting PAs and the invasiveness of PAs.
CONCLUSION: The different NDRG2 promoter methylation and expression levels in PA samples showed tumor heterogeneity and indicates a potential role of this gene in pituitary adenoma pathogenesis, but the corresponding details require intensive research.

Tamura T, Ichikawa T, Nakahata S, et al.
Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential.
Cancer Res. 2017; 77(9):2363-2374 [PubMed] Related Publications
Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here, we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. In

Chung LC, Chiang KC, Feng TH, et al.
Caffeic acid phenethyl ester upregulates N-myc downstream regulated gene 1 via ERK pathway to inhibit human oral cancer cell growth in vitro and in vivo.
Mol Nutr Food Res. 2017; 61(9) [PubMed] Related Publications
SCOPE: Caffeic acid phenethyl ester (CAPE), a bioactive component of propolis, is considered as a new anti-cancer agent. Oral squamous cell carcinoma (OSCC) is the most common oral cancer with unsatisfying survival. N-myc downstream regulated family genes (NDRGs) involve in numerous physiological processes. We investigated the anti-cancer effect of CAPE on OSCC and related mechanisms.
METHODS AND RESULTS: Cell proliferation assay, western blot, gene transfection and knockdown, and reporter assay were applied. We showed that CAPE attenuated OSCC cell proliferation and invasion in vitro, and safely and effectively inhibited OSCC cell growth in a xenograft animal model. CAPE treatment induced NDRG1, but not NDRG2 and NDRG3, expression in OSCC cells as determined by western blot, RT-qPCR, and reporter assay. The 5'-deletion assay demonstrated that CAPE increased NDRG1 promoter activity depending on the region of -128 to +46 of the 5'-flanking of NDRG1 gene. NDRG1 gene knockdown attenuated CAPE anti-growth effect on OSCC cells. CAPE activated mitogen-activated protein kinase (MAPK) signaling pathway. The extracellular signal regulated kinase (ERK) inhibitor (PD0325901) and ERK1 knockdown blocked CAPE-induced NDRG1 expression in OSCC cells.
CONCLUSION: CAPE activated MAPK signaling pathway and increased NDRG1 expression through phosphorylation of ERK1/2 to repress OSCC cells growth.

Lango-Chavarría M, Chimal-Ramírez GK, Ruiz-Tachiquín ME, et al.
A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients.
Int J Oncol. 2017; 50(2):432-440 [PubMed] Free Access to Full Article Related Publications
Breast cancer ranks first in incidence and mortality in working age women. Cancer initiation and progression relies on accumulation of genetic and epigenetic aberrations that alter cellular processes, among them, epithelial to mesenchymal transition (EMT) denotes particularly aggressive neoplasias given its capacity to invade and metastasize. Several microRNAs (miRNA) have been found able to regulate gene expression at the core of EMT. In this study, the Affymetrix CytoScan HD array was used to analyze three different primary tumor cell isolates from Mexican breast cancer patients. We found an amplification in band 22q11.2 shared by the three samples, in the region that encodes miRNA-650. Overexpression of this miRNA has been associated with downregulation of tumor suppressors ING4 and NDRG2, which have been implicated in cancer progression. Using the Pathway Linker platform the ING4 and NDRG2 interaction networks showed a significant association with signaling pathways commonly deregulated in cancer. Also, several studies support their participation in the EMT. Supporting the latter, we found that the three primary isolates were E-cadherin negative, vimentin positive, presented a cancer stem cell-like phenotype CD44+CD24-/low and were invasive in Transwell invasion assays. This evidence suggests that the gain of region 22q11.2 contributes to trigger EMT. This is the first evidence linking miR-650 and breast cancer.

Yamamura A, Miura K, Karasawa H, et al.
NDRG2, suppressed expression associates with poor prognosis in pancreatic cancer, is hypermethylated in the second promoter in human gastrointestinal cancers.
Biochem Biophys Res Commun. 2017; 484(1):138-143 [PubMed] Related Publications
Although N-myc downstream regulated gene 2 (NDRG2) is frequently downregulated in various cancers and is considered to be a candidate tumor suppressor gene, molecular mechanisms of the expressional suppression that lead to cancers are largely unknown. Recent studies indicated that epigenetic suppression of NDRG2 involved carcinogenesis and progression in several tumor types, and we demonstrated positive association with NDRG2 suppression and poor prognosis in pancreatic cancer. In this study, we analyzed mRNA and protein expressions of NDRG2 in 26 cancer cell lines (20 colorectal and 6 gastric cancers) and found that many cell lines showed variously reduced NDRG2 expressions. Furthermore, NDRG2 expressions were significantly reduced in primary resected cancer tissues compared to corresponding normal tissues immunohistochemically (19 of 20 colorectal and 14 of 17 gastric cancers). Treatment with 5-Aza-2' deoxycytidine predominantly upregulated NDRG2 expressions in NDRG2 low-expressing cell lines. Bisulfite sequencing analyses and methylation specific PCR revealed that methylation status at one of the two promoters (around exon 2) correlated well with the suppressed expression, and this is the major promoter in colorectal and gastric cancer cell lines. Our present results suggest that hypermethylation in promoter around exon 2 is functioning as essential factors of NDRG2 silencing in gastrointestinal cancers.

Pan T, Zhang M, Zhang F, et al.
NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation.
Biochem Biophys Res Commun. 2017; 483(2):860-866 [PubMed] Related Publications
Because of the high nutrient consumption and inadequate vascularization, solid tumor constantly undergoes metabolic stress during tumor development. Oncogenes and tumor suppressor genes participated in cancer cells' metabolic reprogramming. N-Myc downstream regulated gene 2 (NDRG2) is a recently identified tumor suppressor gene, but its function in cancer metabolism, particularly during metabolic stress, remains unclear. In this study, we found that NDRG2 overexpression significantly reduced hepatoma cell proliferation and enhanced cell apoptosis under glucose limitation. Moreover, NDRG2 overexpression aggravated energy imbalance and oxidative stress by decreasing the intracellular ATP and NADPH generation and increasing ROS levels. Strikingly, NDRG2 inhibited the activation of fatty acid oxidation (FAO), which preserves ATP and NADPH purveyance in the absence of glucose. Finally, mechanistic investigation showed that NDRG2 overexpression suppressed the glucose-deprivation induced AMPK/ACC pathway activation in hepatoma cells, whereas the expression of a constitutively active form of AMPK abrogated glucose-deprivation induced AMPK activation and cell apoptosis. Thus, as a negative regulator of AMPK, NDRG2 disturbs the induction of FAO genes by glucose limitation, leading to dysregulation of ATP and NADPH, and thus reduces the tolerance of hepatoma cells to glucose limitation.

Chiang KC, Yeh TS, Wu RC, et al.
Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker.
Sci Rep. 2016; 6:36138 [PubMed] Free Access to Full Article Related Publications
Cholangiocarcinoma (CCA) is a devastating disease due to resistance to traditional chemotherapies and radiotherapies. New therapeutic strategies against CCA are urgently needed. This study investigated the role of lipocalin-2 (LCN2) in human cholangiocarcinoma as a potential therapeutic target and diagnostic marker. So far, the role of LCN2 in cancer is still controversial and studies regarding the role of LCN2 in CCA are limited. LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of cell cycle arrest at G0/G1 phases and decreased metastatic potential due to repression of epithelial-mesenchymal transition (EMT). Overexpression of LCN2 in CCA cells increased cell metastatic potential. We showed for the first time that the N-myc downstream regulated gene 1 (NDRG1) and NDRG2, known as tumor suppressor genes, are negatively regulated by LCN2 in CCA cells. LCN2 concentration in bile was higher in patients with CCA than that in patients with gallstones, with a cutoff value of 20.08 ng/ml making this a potential diagnostic marker. Higher LCN2 expression was associated with worse survival in patients with CCA. LCN2 is a promising target for CCA treatment and bile LCN2 level is a potential diagnostic marker for CCA.

Wang J, Xie C, Pan S, et al.
N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway.
Hepatology. 2016; 64(5):1606-1622 [PubMed] Related Publications
Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients.
CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).

Kloten V, Schlensog M, Eschenbruch J, et al.
Abundant NDRG2 Expression Is Associated with Aggressiveness and Unfavorable Patients' Outcome in Basal-Like Breast Cancer.
PLoS One. 2016; 11(7):e0159073 [PubMed] Free Access to Full Article Related Publications
NDRG2, a member of the N-myc downstream-regulated gene family, is thought to be a putative tumor suppressor gene with promising clinical impact in breast cancer. Since breast cancer comprises heterogeneous intrinsic subtypes with distinct clinical outcomes we investigated the pivotal role of NDRG2 in basal-type breast cancers. Based on subtype classified tumor (n = 45) and adjacent normal tissues (n = 17) we examined NDRG2 mRNA expression and CpG-hypermethylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA). In addition, NDRG2 protein expression was evaluated immunohistochemically using a tissue micro array (TMA, n = 211). In vitro, we investigated phenotypic effects caused by NDRG2 silencing in the basal A-like HCC1806 as well as NDRG2 over-expression in basal A-like BT20 compared to luminal-type MCF7 breast cancer cells. Our tissue collections demonstrated an overall low NDRG2 mRNA expression in breast cancer subtypes compared to normal breast tissue in line with an increased CpG-hypermethylation in breast cancer tissue. Independent TCGA data sets verified a significant (P<0.001) expression loss of NDRG2 in breast tumors. Of interest, basal-like tumors more frequently retained abundant NDRG2 expression concordant with a lower CpG-hypermethylation. Unexpectedly, basal-like breast cancer revealed an association of NDRG2 expression with unfavorable patients' outcome. In line with this observation, in vitro experiments demonstrated reduced proliferation and migration rates (~20%) in HCC1806 cells following NDRG2 silencing. In contrast, NDRG2 over-expressing luminal-type MCF7 cells demonstrated a 26% decreased proliferation rate. Until now, this is the first study investigating the putative role of NDRG2 in depth in basal-type breast cancer. Our data indicate that the described putative tumor suppressive function of NDRG2 may be confined to luminal- and basal B-type breast cancers.

Wang W, Liu M, Guan Y, Wu Q
Hypoxia-Responsive Mir-301a and Mir-301b Promote Radioresistance of Prostate Cancer Cells via Downregulating NDRG2.
Med Sci Monit. 2016; 22:2126-32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND MiR-301a and miR-301b are 2 oncomiRs involved in multiple types of cancer. In this study, we explored the expression change of miR-301a and miR-301b in prostate cancer cells in hypoxia and studied their regulation of autophagy and radiosensitivity of prostate cancer cells. MATERIAL AND METHODS QRT-PCR was performed to quantify the expression change of miR-301a and miR-301b in hypoxia. Their effects on autophagy were measured by Western blot analysis, and their effects on radiosensitivity were measured by clonogenic assay and flow cytometry. In addition, the regulation of miR-301a and miR-301b on NDRG2, a tumor-suppressor gene in prostate cancer, was also studied. The effect of miR-301a/b-NDRG2 axis on autophagy and radiosensitivity of prostate cancer cells was further investigated. RESULTS MiR-301a and miR-301b are 2 hypoxia responsive miRNAs that are significantly upregulated in hypoxia in prostate cancer cells. Higher level of miR-301a and miR-301b expression results in elevated autophagy and increased radioresistance in LNCaP cells. MiR-301a and miR-301b simultaneously target NDRG2 and decrease its expression. Knockdown of NDRG2 leads to increased autophagy and radioresistance. CONCLUSIONS MiR-301a and miR-301b are 2 hypoxia-responsive miRNAs that decrease autophagy of prostate cancer cells in hypoxia by targeting NDRG2. Through downregulating NDRG2, miR-301a and miR-301b can promote radioresistance of prostate cancer cells.

Hu W, Yang Y, Fan C, et al.
Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers.
Apoptosis. 2016; 21(6):675-82 [PubMed] Related Publications
Human N-Myc downstream-regulated gene 2 (NDRG2), located at chromosome 14q11.2, has been reported to be down-regulated and associated with the progression and prognosis of diverse cancers. Collectively, previous studies suggest that NDRG2 functions as a candidate tumor-suppressor gene; thus, up-regulation of NDRG2 protein might act as a promising therapeutic strategy for malignant tumors. The aim of this review was to comprehensively present the clinical and pathological significance of NDRG2 in human cancers.

Tantai J, Pan X, Hu D
RNF4-mediated SUMOylation is essential for NDRG2 suppression of lung adenocarcinoma.
Oncotarget. 2016; 7(18):26837-43 [PubMed] Free Access to Full Article Related Publications
N-Myc downstream-regulated gene 2 (NDRG2) protein is a tumor suppressor that inhibits cancer growth, metastasis and invasion. The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin through its selective recognition and ubiquitination of SUMO-modified proteins. We evaluated NDRG2 SUMOylation in lung adenocarcinoma cells and its underlying molecular mechanism. The results showed that NDRG2 is covalently modified by SUMO1 at K333, which suppressed anchorage independent adenocarcinoma cell proliferation and tumor growth. In human lung adenocarcinomas cells, RNF4 targeted NDRG2 to proteasomal degradation by stimulating its SUMOylation. Endogenous RNF4 expression was increased in human lung adenocarcinomas cells, and there was a concomitant upregulation of SUMO. These findings indicate that SUMOylation of NDRG2 is necessary for its tumor suppressor function in lung adenocarcinoma and that RNF4 increases the efficiency of this process.

Kolodziej MA, Weischer C, Reinges MH, et al.
NDRG2 and NDRG4 Expression Is Altered in Glioblastoma and Influences Survival in Patients with MGMT-methylated Tumors.
Anticancer Res. 2016; 36(3):887-97 [PubMed] Related Publications
AIM: The N-myc down-regulated gene (NDRG) family is a group of genes that have predominantly tumor-suppressive effects. The goal of this study was to investigate the expression of NDRG2 and NDRG4 in surgical specimens of human glioblastoma and in normal brain tissue, and to search for correlations with overall (OS) and progression-free survival (PFS).
MATERIALS AND METHODS: Samples from 44 patients (31 males, 13 females; mean age±SD=57.4±15.7 years) with primary (n=40) or recurrent glioblastoma (n=4) were analyzed by quantitative real-time polymerase chain reaction and immunohistochemistry, with dimensionless semiquantitative immunoreactivity score (IRS), ranging from 0-30] for expression of NDRG2 and NDRG4. Five non-tumorous autopsy brain specimens were used as controls.
RESULTS: On the protein level, expression of NDRG2 was significantly down-regulated in glioblastoma (IRS=3.5±3.0 vs. 8.8±3.3; p=0.001), while expression of NDRG4 was significantly up-regulated (IRS=5.4±3.7 vs. 0.75±0.4 vs, p<0.001). There was no statistically significant difference in PFS between a group of 15 patients with glioblastoma with MGMT methylation and enhanced expression of NDRG4 mRNA who were treated with adjuvant radiochemotherapy (temozolomide and 60 Gy) and a group of patients with low expression of NDRG4 mRNA [10 (range=5.5-14.2) months vs. 21 (range=10.7-31.3) months] (p=0.13).
CONCLUSION: Expression of both NDRG2 and NDRG4 genes is significantly altered in glioblastomas. PFS among the patients with glioblastoma with MGMT methylation treated with radiochemotherapy differed significantly in high-expression groups compared to patients without MGMT methlation and without radiochemotherapy (p<0.05).

Yin A, Wang C, Sun J, et al.
Overexpression of NDRG2 Increases Iodine Uptake and Inhibits Thyroid Carcinoma Cell Growth In Situ and In Vivo.
Oncol Res. 2016; 23(1-2):43-51 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) is an uncommon and highly aggressive tumor of the neuroendocrine system, which derives from the neuroendocrine C cells of the thyroid gland. Except for surgical resection, there are not very many effective systemic treatment options for MTC. N-Myc downstream-regulated gene 2 (NDRG2) had a significantly lower expression in MTC compared with normal thyroid tissue. However, the function of NDRG2 in MTC oncogenesis is largely unknown. In this study, we found that overexpression of NDRG2 inhibited the proliferation of TT cells (human medullary thyroid carcinoma cells) in vitro and suppressed the development of MTC in a nude mouse xenograft model. Further analysis revealed that NDRG2 arrested the cell cycle G0/G1 phase progression and induced TT cell apoptosis. Moreover, NDRG2 overexpression may mediate the antiproliferative effect by reducing cyclin D1 and cyclin E protein levels. We also found aberrant NDRG2-mitigated TT cell migration and invasion in vitro. Sodium/iodide symporter (NIS) mediates active I(-) transport into the thyroid follicular cells, and radionuclide treatment is a promising therapy for MTC. Our current data revealed that NDRG2 overexpression enhanced NIS level in TT cells and increased their iodine uptake in vitro. Furthermore, (99m)TcO4(-) radionuclide imaging of the xenograft tumors indicated that NDRG2 could promote NIS-mediated radionuclide transport. In conclusion, the present study suggested that NDRG2 is a critical molecule in the regulation of MTC biological behavior and a potential promoter in radioactive iodine therapy.

Gödeke J, Luxenburger E, Trippel F, et al.
Low expression of N-myc downstream-regulated gene 2 (NDRG2) correlates with poor prognosis in hepatoblastoma.
Hepatol Int. 2016; 10(2):370-6 [PubMed] Related Publications
BACKGROUND/PURPOSE OF THE STUDY: Despite tremendous progress in therapy, about 30% of patients with hepatoblastoma still succumb to the disease. Thus, the development of improved therapies as well as the identification of prognostic factors are urgently needed.
METHODS: In the present study, expression and promoter methylation of the N-myc downstream-regulated gene (NDRG2), a tumor suppressor gene contributing to the regulation of the Wnt signalling pathway, was analysed in 38 hepatoblastoma samples by real-time reverse transcription-PCR and pyrosequencing, respectively.
RESULTS: The NDRG2 gene was highly expressed in normal pediatric liver tissue, but was significantly downregulated in heptoblastoma primary tumors. Detailed methylation analysis of CpG sites in the NDRG2 promoter region revealed a general high degree of DNA methylation in hepatoblastoma, which correlated with the suppression of NDRG2. By analyzing clinicopathological features we could demonstrate a strong association between low NDRG2 expression and tumor metastasis. Importantly, the overall survival analysis by Kaplan-Meier revealed that high NDRG2 expression was correlated with a higher survival rate in hepatoblastoma patients.
CONCLUSION: Our data show that downregulation of NDRG2 may play an important role in advanced hepatoblastomas.

Hu W, Fan C, Jiang P, et al.
Emerging role of N-myc downstream-regulated gene 2 (NDRG2) in cancer.
Oncotarget. 2016; 7(1):209-23 [PubMed] Free Access to Full Article Related Publications
N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor and cell stress-related gene. NDRG2 is associated with tumor incidence, progression, and metastasis. NDRG2 regulates tumor-associated genes and is regulated by multiple conditions, treatments, and protein/RNA entities, including hyperthermia, trichostatin A and 5-aza-2'-deoxycytidine, which are promising potential cancer therapeutics. In this review, we discuss the expression as well as the clinical and pathological significance of NDRG2 in cancer. The pathological processes and molecular pathways regulated by NDRG2 are also summarized. Moreover, mechanisms for increasing NDRG2 expression in tumors and the potential directions of future NDRG2 research are discussed. The information reviewed here should assist in experimental design and increase the potential of NDRG2 as a therapeutic target for cancer.

Xu X, Li J, Sun X, et al.
Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.
Oncotarget. 2015; 6(28):26161-76 [PubMed] Free Access to Full Article Related Publications
Cancer cells use glucose and glutamine as the major sources of energy and precursor intermediates, and enhanced glycolysis and glutamimolysis are the major hallmarks of metabolic reprogramming in cancer. Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect glycolysis and glutaminolysis. N-Myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene inhibiting cancer growth, metastasis and invasion. However, the role and molecular mechanism of NDRG2 in cancer metabolism remains unclear. In this study, we discovered the role of the tumor suppressor gene NDRG2 in aerobic glycolysis and glutaminolysis of cancer cells. NDRG2 inhibited glucose consumption and lactate production, glutamine consumption and glutamate production in colorectal cancer cells. Analysis of glucose transporters and the catalytic enzymes involved in glycolysis revealed that glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase A (LDHA) was significantly suppressed by NDRG2. Analysis of glutamine transporter and the catalytic enzymes involved in glutaminolysis revealed that glutamine transporter ASC amino-acid transporter 2 (ASCT2) and glutaminase 1 (GLS1) was also significantly suppressed by NDRG2. Transcription factor c-Myc mediated inhibition of glycolysis and glutaminolysis by NDRG2. More importantly, NDRG2 inhibited the expression of c-Myc by suppressing the expression of β-catenin, which can transcriptionally activate C-MYC gene in nucleus. In addition, the growth and proliferation of colorectal cancer cells were suppressed significantly by NDRG2 through inhibition of glycolysis and glutaminolysis. Taken together, these findings indicate that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-Myc, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic enzymes involved in glycolysis and glutaminolysis, which fuels the bioenergy and biomaterials needed for cancer proliferation and progress.

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