title: Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene.
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.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute-Porto, Porto, Portugal.
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: Paula
authors.initials: P
authors.lastname: Paulo
authors.forename: Vera L
authors.initials: VL
authors.lastname: Costa
authors.forename: João D
authors.initials: JD
authors.lastname: Barros-Silva
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012471:Salivary Proteins and Peptides / Q000235:genetics* / Q000378:metabolism; D029589:Seminal Plasma Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C489926:CRISP3 protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012471:Salivary Proteins and Peptides; D029589:Seminal Plasma Proteins; C515553:TMPRSS2-ERG fusion protein, human