Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene

PLoS One. 2011;6(7):e22317. doi: 10.1371/journal.pone.0022317. Epub 2011 Jul 21.

Abstract

A large percentage of prostate cancers harbor TMPRSS2-ERG gene fusions, leading to aberrant overexpression of the transcription factor ERG. The target genes deregulated by this rearrangement, however, remain mostly unknown. To address this subject we performed genome-wide mRNA expression analysis on 6 non-malignant prostate samples and 24 prostate carcinomas with (n = 16) and without (n = 8) TMPRSS2-ERG fusion as determined by FISH. The top-most differentially expressed genes and their associations with ERG over-expression were technically validated by quantitative real-time PCR and biologically validated in an independent series of 200 prostate carcinomas. Several genes encoding metabolic enzymes or extracellular/transmembrane proteins involved in cell adhesion, matrix remodeling and signal transduction pathways were found to be co-expressed with ERG. Within those significantly over-expressed in fusion-positive carcinomas, CRISP3 showed more than a 50-fold increase when compared to fusion-negative carcinomas, whose expression levels were in turn similar to that of non-malignant samples. In the independent validation series, ERG and CRISP3 mRNA levels were strongly correlated (r(s) = 0.65, p<0.001) and both were associated with pT3 disease staging. Furthermore, immunohistochemistry results showed CRISP3 protein overexpression in 63% of the carcinomas and chromatin immunoprecipitation with an anti-ERG antibody showed that CRISP3 is a direct target of the transcription factor ERG. We conclude that ERG rearrangement is associated with significant expression alterations in genes involved in critical cellular pathways that define a subset of locally advanced PCa. In particular, we show that CRISP3 is a direct target of ERG that is strongly overexpressed in PCa with the TMPRSS2-ERG fusion gene.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Case-Control Studies
  • Chromatin Immunoprecipitation
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Hyperplasia / genetics*
  • Prostatic Hyperplasia / metabolism
  • Prostatic Hyperplasia / pathology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Salivary Proteins and Peptides / genetics*
  • Salivary Proteins and Peptides / metabolism
  • Seminal Plasma Proteins / genetics*
  • Seminal Plasma Proteins / metabolism
  • Up-Regulation

Substances

  • Biomarkers, Tumor
  • CRISP3 protein, human
  • Oncogene Proteins, Fusion
  • RNA, Messenger
  • Salivary Proteins and Peptides
  • Seminal Plasma Proteins
  • TMPRSS2-ERG fusion protein, human