RESUMEN
Overexpression of TOP2A is associated with risk of systemic progression in prostate cancer patients, and higher levels of TOP2A were found in hormone-resistant cases. To elucidate the mechanism by which high levels of TOP2A contribute to tumor progression we generated TOP2A overexpressing prostate cancer cell lines. We show that TOP2A promotes tumor aggressiveness by inducing chromosomal rearrangements of genes that contribute to a more invasive phenotype. Anti-androgen treatment alone was ineffective in killing TOP2A overexpressing cells due to activation of an androgen receptor network. TOP2A poisons killed tumor cells more efficiently early in the progression course, while at later stages they provided greater benefit when combined with anti-androgen therapy. Mechanistically, we find that TOP2A enhances androgen signaling by facilitating transcription of androgen responsive genes, thereby promoting tumor cell growth. These studies revealed a relationship between TOP2A and androgen receptor signaling pathway that contributes to prostate cancer progression and confers sensitivity to treatments.
Asunto(s)
Adenocarcinoma/metabolismo , Antígenos de Neoplasias/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Invasividad Neoplásica/patología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Adenocarcinoma/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de Unión a Poli-ADP-Ribosa , Neoplasias de la Próstata/patología , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: Autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for neuromyelitis optica (NMO). Therefore, we evaluated whether AQP4 single-nucleotide polymorphisms (SNPs) are associated with susceptibility to NMO or whether mutations that potentially alter AQP4 structure or expression are present in some patients. METHODS: We genotyped 8 AQP4 SNPs chosen based on their minor allele frequency, location, and novelty in 177 NMO sporadic cases, 14 NMO familial cases, and 1,363 matched controls by TaqMan-based assay. We performed bidirectional sequencing of the promoter (1 kb), exons 0-4, and flanking splice consensus sequences, and the 5' and 3' untranslated regions of 177 sporadic and 14 familial NMO cases. RESULTS: One of 8 SNPs (minor allele frequency = 0.01) was associated with NMO (NC 18.8; chrom pos. 22695167: T>A): odds ratio (95% confidence interval) = 13.1 (1.4-126.7); p = 0.026. In 3 patients with NMO (2 related), we detected 2 different missense allelic mutations at Arg19 (R19I and R19T). None of the 1,363 control subjects had Arg19 mutations (p = 0.001). CONCLUSIONS: Except for one uncommon SNP, no tested SNP was associated with NMO, nor were 3 SNP haplotypes, providing no support for the hypothesis that genetic variation in AQP4 accounts for overall susceptibility to NMO. Two different allelic Arg19 missense mutations are specific to NMO and segregated with the disease in one pedigree. Although the pathobiology underlying this is not yet established, their effects on the structure of the M1 isoform N terminus or the regulatory sequence of the M23 isoform by virtue of their location support a role of AQP4 orthogonal array formation on molecular susceptibility to NMO.
Asunto(s)
Acuaporina 4/genética , Estudio de Asociación del Genoma Completo/métodos , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/genética , Adolescente , Adulto , Anciano , Acuaporina 4/inmunología , Autoanticuerpos/biosíntesis , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
The authors studied the association of an exon 4 (E4*epsilon2/3/4) and three promoter polymorphisms of APOE with disease course and severity stratified by gender in 221 patients with multiple sclerosis from two overlapping population-based prevalence cohorts. Women carriers of the E4*epsilon2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles epsilon3 or epsilon4 and promoter polymorphisms were not associated with disease course or severity.