Decrease and gain of gene expression are equally discriminatory markers for prostate carcinoma: a gene expression analysis on total and microdissected prostate tissue.

Information on over- and underexpressed genes in prostate cancer in comparison to adjacent normal tissue was sought by DNA microarray analysis. Approximately 12,600 mRNA sequences were analyzed from a total of 26 tissue samples (17 untreated prostate cancers, 9 normal adjacent to prostate cancer tissues) obtained by prostatectomy. Hierarchical clustering was performed. Expression levels of 63 genes were found significantly (at least 2.5-fold) increased, whereas expression of 153 genes was decreased (at least 2.5-fold) in prostate cancer versus adjacent normal tissue. In addition to previously described genes such as hepsin, overexpression of several genes was found that has not drawn attention before, such as the genes encoding the specific granule protein (SGP28), alpha-methyl-acyl-CoA racemase, low density lipoprotein (LDL)-phospholipase A2, and the anti-apoptotic gene PYCR1. The radiosensitivity gene ATDC and the genes encoding the DNA-binding protein inhibitor ID1 and the phospholipase inhibitor uteroglobin were significantly down-regulated in the cancer samples. DNA microarray data for eight genes were confirmed quantitatively in five normal and five cancer tissues by real-time reverse transcriptase-polymerase chain reaction with a high correlation between the two methods. Laser capture microdissection of epithelial and stromal compartments from cancer and histological normal specimens followed by an amplification protocol for low levels of RNA (<0.1 microg) allowed us to distinguish between gene expression profiles characteristic of epithelial cells and those typical of stroma. Most of the genes identified in the nonmicrodissected tumor material as up-regulated were indeed overexpressed in cancerous epithelium rather than in the stromal compartment. We conclude that development of prostate cancer is associated with down-regulation as well as up-regulation of genes that show complex differential regulation in epithelia and stroma. Some of the gene expression alterations identified in this study may prove useful in the development of novel diagnostic and therapeutic strategies.

[1]  E. Brown,et al.  Quantitative analysis of mRNA amplification by in vitro transcription. , 2001, Nucleic acids research.

[2]  E. Baldi,et al.  Uteroglobin reverts the transformed phenotype in the endometrial adenocarcinoma cell line HEC‐1A by disrupting the metabolic pathways generating platelet‐activating factor , 2000, International journal of cancer.

[3]  T. Stamey,et al.  Biological determinants of cancer progression in men with prostate cancer. , 1999, JAMA.

[4]  L. Jacobs,et al.  Fatty acid synthesis: a potential selective target for antineoplastic therapy. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Cornford,et al.  The cellular and molecular basis of prostate cancer , 1999, BJU international.

[6]  H. Höfler,et al.  Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue. , 2001, The American journal of pathology.

[7]  B. Cairns.  Emerging roles for chromatin remodeling in cancer biology. , 2001, Trends in cell biology.

[8]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[9]  H. Moch,et al.  Genetic changes in clinically organ-confined prostate cancer by comparative genomic hybridization. , 2000, Urology.

[10]  W. Heston.  Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. , 1997, Urology.

[11]  Y. Chen,et al.  Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells. , 2001, Carcinogenesis.

[12]  K. Sadler.  Steroid hormones send a signal. , 2001, Trends in cell biology.

[13]  W. Isaacs,et al.  Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. , 2001, Cancer Research.

[14]  S. Segerer,et al.  Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. , 2000, Journal of the American Society of Nephrology : JASN.

[15]  R. Miller,et al.  Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Epstein,et al.  Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. , 1999, The American journal of pathology.

[17]  T. Visakorpi,et al.  Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. , 1995, Cancer research.

[18]  J. E. Rees,et al.  Mutations in the gene encoding peroxisomal α-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy , 2000, Nature Genetics.

[19]  H. Tanke,et al.  Molecular cytogenetic analysis of prostatic adenocarcinomas from screening studies : early cancers may contain aggressive genetic features. , 2001, The American journal of pathology.

[20]  H. Barnes,et al.  Heterologous expression of human uteroglobin/polychlorinated biphenyl-binding protein. Determination of ligand binding parameters and mechanism of phospholipase A2 inhibition in vitro. , 1994, The Journal of biological chemistry.

[21]  G. Muir,et al.  Identification of potential diagnostic markers of prostate cancer and prostatic intraepithelial neoplasia using cDNA microarray , 2001, British Journal of Cancer.

[22]  M. Watson,et al.  Expression Profiling of Ductal Carcinoma in Situ by Laser Capture Microdissection and High-Density O , 2001 .

[23]  M. Bittner,et al.  Human prostate cancer and benign prostatic hyperplasia: molecular dissection by gene expression profiling. , 2001, Cancer research.

[24]  R. Shah,et al.  Postatrophic hyperplasia of the prostate gland: neoplastic precursor or innocent bystander? , 2001, The American journal of pathology.

[25]  Rainer M. Bohle,et al.  Real-time quantitative RT–PCR after laser-assisted cell picking , 1998, Nature Medicine.

[26]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Jeffrey A. Magee,et al.  Expression profiling reveals hepsin overexpression in prostate cancer. , 2001, Cancer research.

[28]  P. Humphrey,et al.  Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. , 1995, The Journal of urology.

[29]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[30]  J. Welsh,et al.  Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. , 2001, Cancer research.

[31]  S. Maxwell,et al.  Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Moch,et al.  Discovery of new DNA amplification loci in prostate cancer by comparative genomic hybridization * , 2001, The Prostate.