Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers.
BACKGROUND
The expression of NDRG1 gene is induced by nickel, a transition metal sharing similar physical properties to cobalt. Nickel may create hypoxia-like conditions in cells and induce hypoxia-responsive genes, as does cobalt. Therefore NDRG1 is likely to be another gene induced by hypoxia. HIF-1 is a transcription factor which has a major role in the regulation of hypoxia-responsive genes, and thus it could be involved in the transcriptional regulation of NDRG1 gene. Hypoxia is such a common feature of solid tumours that it is of interest to investigate the expression of Ndrg1 protein in human cancers.


RESULTS
Hypoxia and its mimetics induce in vitro expression of NDRG1 gene and cause the accumulation of Ndrg1 protein. Protein levels remain high even after cells revert to normoxia. Although HIF-1 is involved in the regulation of NDRG1, long term hypoxia induces the gene to some extent in HIF-1 knock-out cells. In the majority of human tissues studied, Ndrg1 protein is overexpressed in cancers compared to normal tissues and also reflects tumour hypoxia better than HIF-1 protein.


CONCLUSIONS
Hypoxia is an inducer of the NDRG1 gene, and nickel probably causes the induction of the gene by interacting with the oxygen sensory pathway. Hypoxic induction of NDRG1 is mostly dependent on the HIF-1 transcription factor, but HIF-1 independent pathways are also involved in the regulation of the gene during chronic hypoxia. The determination of Ndrg1 protein levels in cancers may aid the diagnosis of the disease.
Cangul
Hakan
H
Department of Medical Genetics, Uludag University School of Medicine, Gorukle, Bursa 16059 Turkey. hcangul@uludag.edu.tr
D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014132:Trachea / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014157:Transcription Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human