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5?-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression.

ABSTRACT: A third isozyme of human 5?-steroid reductase, 5?-reductase-3, was identified in prostate tissue at the mRNA level. However, the levels of 5?-reductase-3 protein expression and its cellular localization in human tissues remain unknown.A specific monoclonal antibody was developed, validated, and used to characterize for the first time the expression of 5?-reductase-3 protein in 18 benign and 26 malignant human tissue types using immunostaining analyses.In benign tissues, 5?-reductase-3 immunostaining was high in conventional androgen-regulated human tissues, such as skeletal muscle and prostate. However, high levels of expression also were observed in non-conventional androgen-regulated tissues, which suggest either multiples target tissues for androgens or different functions of 5?-reductase-3 among human tissues. In malignant tissues, 5?-reductase-3 immunostaining was ubiquitous but particularly over-expressed in some cancers compared to their benign counterparts, which suggests a potential role for 5?-reductase-3 as a biomarker of malignancy. In benign prostate, 5?-reductase-3 immunostaining was localized to basal epithelial cells, with no immunostaining observed in secretory/luminal epithelial cells. In high-grade prostatic intraepithelial neoplasia (HGPIN), 5?-reductase-3 immunostaining was localized in both basal epithelial cells and neoplastic epithelial cells characteristic of HGPIN. In androgen-stimulated and castration-recurrent prostate cancer (CaP), 5?-reductase-3 immunostaining was present in most epithelial cells and at similar levels, and at levels higher than observed in benign prostate. Analyses of expression and functionality of 5?-reductase-3 in human tissues may prove useful for development of treatment for benign prostatic enlargement and prevention and treatment of CaP.

SUBMITTER: Godoy A

PROVIDER: S-EPMC4295561 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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5α-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression.

Godoy Alejandro A Kawinski Elzbieta E Li Yun Y Oka Daizo D Alexiev Borislav B Azzouni Faris F Titus Mark A MA Mohler James L JL

The Prostate 20101228 10

<h4>Background</h4>A third isozyme of human 5α-steroid reductase, 5α-reductase-3, was identified in prostate tissue at the mRNA level. However, the levels of 5α-reductase-3 protein expression and its cellular localization in human tissues remain unknown.<h4>Methods</h4>A specific monoclonal antibody was developed, validated, and used to characterize for the first time the expression of 5α-reductase-3 protein in 18 benign and 26 malignant human tissue types using immunostaining analyses.<h4>Resul ...[more]

PMID: 21557268

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Project description:Intra-tumor heterogeneity (ITH) has been studied at the morphologic, genomic, and transcriptomic level, but not proteomic level. Recent advances in mass spectrometric (MS) proteome quantification techniques, exemplified by SWATH-MS, a massively parallel targeting method, now also support precise quantitative proteomic comparisons across multiple samples, thus identifying molecular and implied functional differences. Here we used SWATH-MS to analyze the proteome profiles of a set of fresh-frozen prostate tissue samples derived from radical prostatectomy specimens. A high confidence set of 1,906 proteins were consistently quantified across 60 biopsy-level tissue samples from three prostatectomy patients, each consisting of 1.0 mm punch biopsies from histologically malignant (acinar and ductal adenocarcinoma) and matching benign prostatic hyperplasia tissues. The quantitative protein profiles allowed independent quantification of the degree of intra-tumor heterogeneity for each protein in benign and malignant tissues. We found that while majority of the proteins showed comparably low intra-tumor variability, 122 proteins were highly variable in malignant and/or matching benign tissues. We observed that proteins that varied between patients or tissue types also tended to be highly variable within prostate tissues, suggesting that these variability patterns will be a critical selection criterion in future protein biomarker studies. The data also permitted investigation of the heterogeneity of multiple biochemical pathways. The high variability of several of the pathways, including Glypican-1 network, alpha-linolenic acid metabolism and celecoxib pathway, explained contradictory results regarding them in the literature. In conclusion, we demonstrated a methodology for investigating proteomic intra-tumor heterogeneity from biopsy-level tissue samples, and quantified the degree of intra-tumor heterogeneity of 1,906 proteins in prostate tumors. The method and data presented here have advanced our understanding of tumor biology and offered critical insights for future biomarker development.

Project description:BackgroundTo study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate tissue.MethodsThe AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-?CT method and correlated to clinicopathological parameters.ResultsTranscripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (??=?-?0.354; p =?0.013), D'Amico risk stratification (??=?-?0.336; p =?0.012), ISUP grade (??=?-?0.321; p =?0.017) and Gleason score (??=?-?0.342; p =?0.011).ConclusionsThis is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.

Dataset Information

5?-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression.

Publications

5α-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression.

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