Subject(s)
B-Lymphocytes/metabolism , Cell Differentiation/immunology , Immunoglobulins/history , Transcription Factors/history , Zinc Fingers , Amino Acid Sequence , Animals , B-Lymphocytes/immunology , Base Sequence , Cell Differentiation/genetics , Cell Line, Tumor , Cloning, Molecular , History, 20th Century , Immunoglobulins/biosynthesis , Immunoglobulins/genetics , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Molecular Sequence Data , Positive Regulatory Domain I-Binding Factor 1 , Transcription Factors/physiology , Transfection/history , Zinc Fingers/genetics , Zinc Fingers/immunologyABSTRACT
We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.
Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Gene Expression Regulation, Neoplastic , Prostatic Hyperplasia/metabolism , Prostatic Hyperplasia/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Adolescent , Adult , Amino Acid Sequence , Cation Transport Proteins , Cell Membrane/metabolism , Disease Progression , Humans , Male , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Prostate/physiology , Prostatic Hyperplasia/genetics , Prostatic Neoplasms/genetics , Reference Values , Transport Vesicles/metabolismABSTRACT
Current models of prostate cancer classification are poor at distinguishing between tumors that have similar histopathological features but vary in clinical course and outcome. Here, we applied classical survival analysis to genome-wide gene expression profiles of prostate cancers and preoperative prostate-specific antigen (PSA) levels from each patient, to identify prognostic markers of disease relapse that provide additional predictive value relative to PSA concentration. Three of approximately 200 probesets showing strongest correlation with relapse were identified as the gene for the putative calcium channel protein, trp-p8, with loss of trp-p8 mRNA expression associated with a significantly shorter time to PSA relapse-free survival. We observed subsequently that trp-p8 is lost in the transition to androgen independence in a prostate cancer xenograft model and in prostate cancer tissue from patients treated preoperatively with antiandrogen therapy, suggesting that trp-p8 is androgen regulated, and its loss may be associated with more advanced disease. The identification of trp-p8 and other proteins implicated in the phosphatidylinositol signal transduction pathway that are associated with prostate cancer outcome, both here and in other published work, suggests an integral role for this pathway in prostate carcinogenesis. Thus, our findings demonstrate that multivariable survival analysis can be applied to gene expression profiles of prostate cancers with censored follow-up data and used to identify molecular markers of prostate cancer relapse with strong predictive power and relevance to the etiology of this disease.
