Glioma is the most common type of primary tumor in the central nervous system, and the molecular mechanisms remain elusive. N-myc downstream-regulated gene (NDRG) family is reported to take part in the pathogenesis of various diseases, including some preliminary exploration in glioma. However, there has been no bioinformatics analysis of NDRG family in glioma yet. Herein, we focused on the expression changes of NDRGs with their value in predicting patients' prognoses, upstream regulatory mechanisms (DNA mutation, DNA methylation, transcription factors, and microRNA regulation) and gene enrichment analysis based on co-expressed genes with data from public databases. Furthermore, the expression pattern of NDRGs was verified by the paired glioma and peritumoral samples in our institute. It was suggested that NDRGs were differentially expressed genes in glioma. In particular, the lower expression of NDRG2 or NDRG4 could serve as a predictor of higher grade tumor and poorer prognosis. Also, NDRGs might play a crucial role in signal transduction, energy metabolism, and cross-talk among cells in glioma, under the control of a complex regulatory network. This study enables us to better understand the role of NDRGs in glioma and with further research, it may contribute to the development of glioma treatment.
Get full access to this article
View all access options for this article.
References
1.
BaoZ., ChenH., YangM., ZhangC., YuK., YeW., et al. (2014). RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res, 24, 1765–1773.
2.
BellE.H., ZhangP., FisherB.J., MacdonaldD.R., McElroyJ.P., LesserG.J., et al. (2018). Association of MGMT promoter methylation status with survival outcomes in patients with high-risk glioma treated with radiotherapy and temozolomide. JAMA Oncol 4,1405.
3.
BeneshE.C., MillerP.M., PfaltzgraffE.R., Grega-LarsonN.E., HagerH.A., SungB.H., et al. (2013). Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. Mol Biol Cell, 24, 3496–3510.
4.
BlaesJ., WeilerM., SahmF., HentschelB., OsswaldM., CzabankaM., et al. (2014). NDRG1 prognosticates the natural course of disease in WHO grade II glioma. J Neurooncol, 117, 25–32.
5.
BredelM., BredelC., JuricD., HarshG.R., VogelH., RechtL.D., et al. (2005). Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas. Cancer Res, 65, 8679–8689.
6.
BrennanC.W., VerhaakR.G., McKennaA., CamposB., NoushmehrH., SalamaS.R., et al. (2013). The somatic genomic landscape of glioblastoma. Cell, 155, 462–477.
7.
BrogginiT., WüstnerM., HarmsC., StangeL., BlaesJ., ThoméC., et al. (2016). NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment. Cancer Lett, 380, 568–576.
8.
CeramiE., GaoJ., DogrusozU., GrossB.E., SumerS.O., AksoyB.A., et al. (2012). The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov, 2, 401–404.
9.
ChenL., ZhangN., RenX., HeJ., and LiY. (2018a). miR-103/miR-195/miR-15b regulate SALL4 and inhibit proliferation and migration in glioma. Molecules 23,2938.
10.
ChenX., LiS., KeY., WuS., HuangT., HuW., et al. (2018b). KLF16 suppresses human glioma cell proliferation and tumourigenicity by targeting TFAM. Artif Cells Nanomed Biotechnol, 46(Suppl 1),608–615.
11.
ChenX.L., LeiL., HongL.L., and LingZ.Q. (2018c). Potential role of NDRG2 in reprogramming cancer metabolism and epithelial-to-mesenchymal transition. Histol Histopathol, 33, 655–663.
DingW., ZhangJ., YoonJ., ShiD., FoltzG., and LinB. (2012). NDRG4 is downregulated in glioblastoma and inhibits cell proliferation. OMICS, 16, 263–267.
14.
DuW., LiuX., ChenL., DouZ., LeiX., ChangL., et al. (2015). Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness. Neuro Oncol, 17, 243–253.
15.
FontenasL., De SantisF., Di DonatoV., DegernyC., ChambraudB., Del BeneF., et al. (2016). Neuronal Ndrg4 is essential for nodes of ranvier organization in zebrafish. PLoS Genet 12,e1006459.
16.
FrenchP.J., SwagemakersS.M., NagelJ.H., KouwenhovenM.C., BrouwerE., van der SpekP., et al. (2005). Gene expression profiles associated with treatment response in oligodendrogliomas. Cancer Res, 65, 11335–11344.
17.
GaoJ., AksoyB.A., DogrusozU., DresdnerG., GrossB., SumerS.O., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6,l1.
18.
GoldmanM., CraftB., HastieM., RepečkaK., McDadeF., KamathA., et al. (2019). The UCSC Xena platform for public and private cancer genomics data visualization and interpretation. bioRxiv,326470.
19.
GTEx Consortium. (2015). Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.Science, 348, 648.
20.
HuY., LiY., WuC., ZhouL., HanX., WangQ., et al. (2017). MicroRNA-140-5p inhibits cell proliferation and invasion by regulating VEGFA/MMP2 signaling in glioma. Tumor Biol 39,568835941.
21.
ItoH., WatariK., ShibataT., MiyamotoT., MurakamiY., NakaharaY., et al. (2020). Bidirectional regulation between NDRG1 and GSK3β controls tumor growth and is targeted by differentiation inducing factor-1 in glioblastoma. Cancer Res, 80, 234–248.
22.
JinJ., ZhangS., HuY., ZhangY., GuoC., and FengF. (2019). SP1 induced lncRNA CASC11 accelerates the glioma tumorigenesis through targeting FOXK1 via sponging miR-498. Biomed Pharmacother 116,108968.
23.
KolodziejM.A., WeischerC., ReingesM.H.T., UhlE., WeigandM.A., SchwarmF.P., et al. (2016). NDRG2 and NDRG4 expression is altered in glioblastoma and influences survival in patients with MGMT-methylated tumors. Anticancer Res 36,887.
24.
KozomaraA., BirgaoanuM., and Griffiths-JonesS. (2018). miRBase: from microRNA sequences to function. Nucleic Acids Res 47,D155.
25.
LaiL.C., SuY.Y., ChenK.C., TsaiM.H., SherY.P., LuT.P., et al. (2011). Down-regulation of NDRG1 promotes migration of cancer cells during reoxygenation. PLoS One 6,e24375.
26.
Le RhunE., PreusserM., RothP., ReardonD.A., van den BentM., WenP., et al. (2019). Molecular targeted therapy of glioblastoma. Cancer Treat Rev 80,101896.
27.
LeeJ., KotliarovaS., KotliarovY., LiA., SuQ., DoninN.M., et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell, 9, 391–403.
28.
LiL., QinX., ShiM., MiaoR., WangL., LiuX., et al. (2012). Regulation of histone acetylation by NDRG2 in glioma cells. J Neurooncol, 106, 485–492.
29.
LiL., WangJ., ShenX., WangL., LiX., LiuY., et al. (2011a). Expression and prognostic value of NDRG2 in human astrocytomas. J Neurol Sci, 308, 77–82.
30.
LiS., YangB., LiG., HeS., and LiY. (2013). Downregulation of N-Myc downstream-regulated gene 4 influences patient survival in gliomas. Brain Tumor Pathol, 30, 8–14.
31.
LiW., ChuD., ChuX., MengF., WeiD., LiH., et al. (2011b). Decreased expression of NDRG2 is related to poor overall survival in patients with glioma. J Clin Neurosci, 18, 1534–1537.
32.
LiuX., LiY., QianZ., SunZ., XuK., WangK., et al. (2018). A radiomic signature as a non-invasive predictor of progression-free survival in patients with lower-grade gliomas. Neuroimage Clin, 20, 1070–1077.
33.
LuoQ., WangC.Q., YangL.Y., GaoX.M., SunH.T., ZhangY., et al. (2018). FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett, 417, 21–34.
34.
MaJ., LiuW., GuoH., LiS., CaoW., DuX., et al. (2014). N-myc downstream-regulated gene 2 expression is associated with glucose transport and correlated with prognosis in breast carcinoma. Breast Cancer Res 16,R27.
35.
MaW., NaM., TangC., WangH., and LinZ. (2015). Overexpression of N-myc downstream-regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3-kinase/AKT pathways. Mol Med Rep, 12, 1050–1058.
36.
MaY., WuL., LiuX., XuY., ShiW., LiangY., et al. (2017). KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling. Oncol Rep, 38, 975–984.
37.
MelotteV., QuX., OngenaertM., CriekingeW., BruïneA.P., BaldwinH.S., et al. (2010). The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J, 24, 4153–4166.
38.
MengQ., LiS., LiuY., ZhangS., JinJ., ZhangY., et al. (2019). Circular RNA circSCAF11 accelerates the glioma tumorigenesis through the miR-421/SP1/VEGFA axis. Mol Ther Nucleic Acids, 17, 669–677.
39.
ModhukurV., IljasenkoT., MetsaluT., LokkK., Laisk-PodarT., and ViloJ. (2017). MethSurv: a web tool to perform multivariable survival analysis using DNA methylation data. Epigenomics, 10, 277–288.
40.
MuratA., MigliavaccaE., GorliaT., LambivW.L., ShayT., HamouM.F., et al. (2008). Stem cell-related “self-renewal”. signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol, 26, 3015–3024.
41.
NaborsL.B., PortnowJ., AhluwaliaM., BaehringJ., BremH., BremS., et al. (2020). Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 18, 1537–1570.
42.
OkudaT., KokameK., and MiyataT. (2008). Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem, 56, 175–182.
43.
PanT., ZhangM., ZhangF., YanG., RuY., WangQ., et al. (2017). NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation. Biochem Biophys Res Commun, 483, 860–866.
44.
PeiJ., and GrishinN.V. (2013). A new family of predicted Krüppel-like factor genes and pseudogenes in placental mammals. PLoS One 8,e81109.
45.
RhodesD.R., YuJ., ShankerK., DeshpandeN., VaramballyR., GhoshD., et al. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia, 6, 1–6.
46.
SaidH.M., SafariR., Al-KafajiG., ErnestusR.I., LohrM., KatzerA., et al. (2017). Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells. Oncol Rep, 37, 3625–3634.
47.
SaidH.M., SteinS., HagemannC., PolatB., StaabA., AnackerJ., et al. (2009). Oxygen-dependent regulation of NDRG1 in human glioblastoma cells in vitro and in vivo. Oncol Rep, 21, 237–246.
48.
SakrM., TakinoT., SabitH., NakadaM., LiZ., and SatoH. (2016). miR-150-5p and miR-133a suppress glioma cell proliferation and migration through targeting membrane-type-1 matrix metalloproteinase. Gene, 587, 155–162.
49.
SchillingS.H., HjelmelandA.B., RadiloffD.R., LiuI.M., WakemanT.P., FielhauerJ.R., et al. (2009). NDRG4 is required for cell cycle progression and survival in glioblastoma cells. J Biol Chem, 284, 25160–25169.
50.
SchonkerenS.L., MassenM., van der HorstR., KochA., VaesN., and MelotteV. (2019). Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system. Neurogenetics, 20, 173–186.
51.
ShaiR., ShiT., KremenT.J., HorvathS., LiauL.M., CloughesyT.F., et al. (2003). Gene expression profiling identifies molecular subtypes of gliomas. Oncogene, 22, 4918–4923.
52.
SunB., ChuD., LiW., ChuX., LiY., WeiD., et al. (2009). Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol, 94, 213–219.
53.
SunL., HuiA.M., SuQ., VortmeyerA., KotliarovY., PastorinoS., et al. (2006). Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell, 9, 287–300.
54.
SvenssonE., VidovicK., OlofssonT., Vallon-ChristerssonJ., BorgA., GullbergU., et al. (2007). The Wilms' tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2). DNA Cell Biol, 26, 589–597.
55.
TepelM., RoerigP., WolterM., GutmannD.H., PerryA., ReifenbergerG., et al. (2008). Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma. Int J Cancer, 123, 2080–2086.
56.
TurkalpZ., KaramchandaniJ., and DasS. (2014). IDH mutation in glioma: new insights and promises for the future. JAMA Neurol 71,1319.
57.
UhlenM., ZhangC., LeeS., SjöstedtE., FagerbergL., BidkhoriG., et al. (2017). A pathology atlas of the human cancer transcriptome. Science 357,eaan2507.
58.
WangL., LiuN., YaoL., LiF., ZhangJ., DengY., et al. (2008). NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem, 21, 239–250.
59.
WangS., LuS., GengS., MaS., LiangZ., and JiaoB. (2013). Expression and clinical significance of microRNA-326 in human glioma miR-326 expression in glioma. Med Oncol 30,373.
60.
WangY., QianT., YouG., PengX., ChenC., YouY., et al. (2015). Localizing seizure-susceptible brain regions associated with low-grade gliomas using voxel-based lesion-symptom mapping. Neuro Oncol, 17, 282–288.
61.
WeilerM., BlaesJ., PuschS., SahmF., CzabankaM., LugerS., et al. (2014). mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proc Natl Acad Sci U S A, 111, 409–414.
62.
XuX., LiJ., SunX., GuoY., ChuD., WeiL., et al. (2015). Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression. Oncotarget, 6, 26161–26176.
63.
YangC., WangC., ChenX., ChenS., ZhangY., ZhiF., et al. (2013). Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int J Cancer, 132, 116–127.
64.
YangH.L., GaoY.M., and ZhaoJ.A. (2017). miR1405p inhibits human glioma cell growth and invasion by targeting JAG1. Mol Med Rep, 16, 3634–3640.
65.
YinJ., ShiZ., WeiW., LuC., WeiY., YanW., et al. (2020). MiR-181b suppress glioblastoma multiforme growth through inhibition of SP1-mediated glucose metabolism. Cancer Cell Int 20,69.
66.
ZhangJ., LiF., LiuX., ShenL., LiuJ., SuJ., et al. (2006). The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with theNDRG2 core promoter. J Biol Chem, 281, 39159–39168.
67.
ZhangP., ChenF.Z., JiaQ.B., and HuD.F. (2019). Upregulation of microRNA-133a and downregulation of connective tissue growth factor suppress cell proliferation, migration, and invasion in human glioma through the JAK/STAT signaling pathway. IUBMB Life, 71, 1857–1875.
68.
ZhangR., ZhuJ.C., HuH., LinQ.Y., ShaoW., and JiT.H. (2020). MicroRNA-140-5p suppresses invasion and proliferation of glioma cells by targeting glutamate-ammonia ligase (GLUL). Neoplasma, 67, 371–378.
69.
ZhaoZ., MengF., WangW., WangZ., ZhangC., and JiangT. (2017). Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas. Sci Data 4,170024.
70.
ZhouJ., JiangY., ZhaoJ., ZhangH., FuJ., LuoP., et al. (2020). Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma. Cell Oncol (Dordr), 43, 461–475.
71.
ZhouY., ZhouB., PacheL., ChangM., KhodabakhshiA.H., TanaseichukO., et al. (2019). Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10,1523.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
