NDPK-A, encoded by nm23-H1 (also known as NME1) was the first metastasis suppressor discovered. Much of the attention has been focused on the metastasis-suppressing role of NDPK-A in human tumors, including breast carcinoma and melanoma. However, compelling evidence points to a metastasis-promoting role of NDPK-A in certain tumors such as neuroblastoma and lymphoma. To balance attention on this contrariety of NDPK-A in different cancer types, this review addresses the metastasis-promoting role of NDPK-A in neuroblastoma. Neuroblastoma is an embryonic tumor, arising from neural crest cells that fail to differentiate into the sympathetic nervous system. We summarize and discuss nm23-H1 genetics and the prognosis of neuroblastoma, structural and functional changes associated with the S120G mutation of NDPK-A, as well as the evidence supporting the role of NDPK-A as a metastasis promoter. Also discussed are the NDPK-A relevant molecular determinants of neuroblastoma metastasis, and metastasis-relevant neural crest development. Because of NDPK-A's dichotomous role in tumor metastasis as both a suppressor and a promoter, tumor genome/exome profiles are necessary to identify the molecular drivers of metastasis in the NDPK-A network for developing tumor-specific therapies.
Background: Upregulation of the platelet-derived growth factor receptor-α (PDGFRα) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRα promoter polymorphism and severity of childhood asthma was examined. Methods: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRα gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRα, was assayed by ELISA kits. Results: The genotype distribution of SNP rs1800810 (–1171G/C) in nonallergic asthma was significantly different from controls (p = 0.038), as well as its allele distribution (p = 0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1 + H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR = 1.94, CI = 1.11–3.39, p < 0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p = 0.008, OR = 2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1 ± 62.9 vs. 249.7 ± 97.1 ng/ml, p < 0.05) and nonallergic asthmatic children (113.8 ± 38.0 vs. 256.6 ± 58.3 ng/ml, p < 0.05). Conclusions: The developmental deficiency due to the low expression of PDGFRα may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRα expression that might lead to airway remodeling causing the severity of asthma.
Altered expression and mutations of NDP kinase A (NDPK-A), encoded by nm23-H1, have been detected in patients with metastatic tumors. One of new functions of NDPK-A is to participate in gene regulation. However, its role in regulating c-myc transcription remains unclear. Here we demonstrate for the first time that NDPK-A specifically bound nuclease hypersensitive element (NHE) III1 of the c-myc promoter in vitro and in vivo. Metastasis-associated S120G mutation of NDPK-A (NDPK-AS120G), but not S120G and N82S double mutations (NDPK-AS120G/N82S), retained the DNA-binding activity. In human NB69 neuroblastoma and HeLa cervical cancer cells, a high level of ectopic NDPK-A or NDPK-AS120 suppressed c-myc transcription based on the CAT reporter and RT-PCR. In contrast, shRNA-mediated knockdown of NDPK-A enhanced c-myc transcription. Without the DNA-binding activity, however, NDPK-AS120G/N82S did not display an effect on c-myc transcription. NDPK-A appears to exert transcriptional suppression via not only NHE III1 but also upstream cis-element(s) of c-myc promoter. The role of NDPK-A in regulating c-myc transcription was supported by nuclear localization of NDPK-A in cells and by negative correlation of NDPK-A and c-myc mRNA levels in several human cancer subtypes. Our findings provide a link between NDPK-A alterations and c-myc transcriptional deregulation in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4074.
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