RESUMEN
BACKGROUND: Proliferative inflammatory atrophy (PIA) has been proposed as a potential precursor for prostate cancer. The precise molecular abnormalities in prostatic atrophy compared to high-grade prostatic intraepithelial neoplasia (HGPIN) and carcinoma have not been fully defined. METHODS: We utilized laser capture microdissection and microarray analysis to characterize cells of PIA, HGPIN, invasive prostatic carcinoma, and non-atrophic benign prostatic epithelium (NABE). Cytoglobin was selected for immunohistochemistry (IHC) validation. IHC stains were evaluated for proportion of positive glands, and intensity of cytoglobin staining. An immunoreactive score (IR score) was determined as the product of the percentage of positive staining and intensity. RESULTS: Microarray analysis revealed probe sets that separated the microdissected cell types. Several genes showed overlapping expression patterns between PIA and PIN, and HGPIN and invasive carcinoma. Cytoglobin protein expression was detected in 57/93 (61%) of NABE and BPH cases, 92/93 atrophy (99%), 3/34 (9%) of PIN, and 23/61 carcinoma (37%) samples. The highest IHC scores were calculated for atrophy foci. A subset (33%) of atrophy cases showed the same low-cytoglobin expression level as PIN and carcinoma. CONCLUSIONS: Prostatic epithelium can be stratified into normal, atrophic, PIN, and invasive carcinoma categories based on differential genetic signatures. Cytoglobin, a protein that can be induced in response to oxidative stress, was elevated in most atrophy foci, suggesting hypoxic, and/or oxidative damage. The lower level of cytoglobin seen in neoplastic cells and 33% of atrophy foci may indicate a shared susceptibility to oxidative damage for this subset of atrophy cases and prostatic neoplasia.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Globinas/biosíntesis , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Adenocarcinoma/metabolismo , Atrofia , Hipoxia de la Célula/fisiología , Citoglobina , Globinas/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Masculino , Estrés Oxidativo/fisiología , Neoplasias de la Próstata/metabolismoRESUMEN
Transcription factor haploinsufficiency plays a role in the pathogenesis of many diseases, including cancer. In a mouse model of prostate tumor initiation, loss of a single allele of the tumor suppressor Nkx3.1 stochastically inactivates the expression of a class of dosage-sensitive target genes. Here we show that dosage sensitivity is associated with the differential histone H3/H4 acetylation states of Nkx3.1 target genes. When histone acetylation is induced in Nkx3.1+/- mouse prostates with the histone deacetylase inhibitor Trichostatin A, Nkx3.1 can bind to and reactivate the expression of dosage-sensitive target genes. We incorporated our findings into a mathematical model that entails the association of Nkx3.1 with histone acetyltransferase activity. Subsequent experiments indicate that Nkx3.1 associates with and recruits the histone acetyltransferase p300/CREB-binding protein-associated factor to chromatin. Finally, we demonstrate a role for the dosage-sensitive target gene intelectin/omentin in suppressing prostate tumorigenicity. Our results reveal how the interplay between transcription factor dosage and chromatin affects target gene expression in tumor initiation.