RESUMO
A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.
Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/genética , DNA Helicases/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Deleção de Genes , Neoplasias da Próstata/genética , Animais , Linhagem Celular , Regulação para Baixo , Células HEK293 , Homozigoto , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , PTEN Fosfo-Hidrolase/genética , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Transplante HeterólogoAssuntos
Transplante de Rim/estatística & dados numéricos , Rim , Doadores Vivos/estatística & dados numéricos , Sistema de Registros , Obtenção de Tecidos e Órgãos/métodos , Honorários e Preços , Teste de Histocompatibilidade , Humanos , Falência Renal Crônica/cirurgia , Transplante de Rim/imunologia , Coreia (Geográfico) , Doadores Vivos/provisão & distribuição , Fatores de RiscoRESUMO
The purpose of this study was to correlate the abnormal signal area on various magnetic resonance (MR) images to the infarct area on pathologic examination and to assess the myocardial viability on the basis of MR images. T2-weighted, first-pass perfusion, and delayed gadolinium-enhanced T1-weighted images were used as "one-stop examinations" in a pig model of reperfused myocardial infarction. The results of each MR image were compared with those of 2,3, 5-triphenyltetrazolium chloride (TTC) staining. The abnormal signal areas on T2-weighted and Gd-enhanced T1-weighted images were larger than the infarct areas on TTC staining (34.7% and 32.3% vs. 28.3%; P< 0.05), whereas the nonperfused areas on perfusion images were correlated (25.6% vs, 28.3%; P = 0.139). Electron microscopic examination showed severely distorted ultrastructures in the infarct areas and mildly damaged ultrastructures in the peri-infarct areas. Perfusion images probably reflected the infarct areas, whereas T2-weighted and Gd-enhanced T1-weighted images seemed to include peri-infarct as well as infarct areas.