NDPKA is not just a metastasis suppressor - be aware of its metastasis-promoting role in neuroblastoma.

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.

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma.

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha 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 PDGFRalpha, 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 PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.

Association of CD14 promoter polymorphisms and soluble CD14 levels in mite allergen sensitization of children in Taiwan.

CD14 is responsible for environmental lipopolysaccharide recognition and is a positional candidate gene for allergy. We hypothesized that genetic polymorphisms in the promoter region of the CD14 gene may be associated with Dermatophagoides pteronysinnus (Der p) allergen sensitization in children. Three single nucleotide polymorphisms (SNPs) of the CD14 promoter region, C(-159)T, A(-1,145)G, and G(-1,359)T were genotyped, and analyzed in 240 randomized case-control school-age children in Taiwan. Serum concentrations of IgE and soluble CD14 (sCD14) were also assayed. We found a significant inverse correlation of sCD14 and total serum IgE levels in our study population. Moreover, sCD14 binds Der p allergen in vitro in a dose-dependent manner. The distribution of three SNPs genotypes was similar in asthmatic children and the control group. However, there was a significant difference in the distribution of genotype CD14 G(-1,359)T, but not C(-159)T, between mite-sensitive and non-sensitive children. Haplotype analysis showed strong linkage disequilibrium among these three SNPs in the CD14 promoter region. Carriers of the CD14-159C/-1,145A/-1,359T haplotype had the highest IgE and lowest sCD14 levels as compared to other haplotypes. Our results support the hypothesis that CD14 gene variants may play an important role in influencing allergen sensitization of children in Taiwan.