Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: From experimental discovery to validation in two independent patient cohorts
Abstract
BACKGROUND
We have previously shown that the long non-coding (lnc)RNAprostate cancer associated 3(PCA3; formerlyprostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor genePRUNE2(a homolog of theDrosophila prunegene), thereby forming a functional unit within a unique allelic locus in human cells. Here we investigated thePCA3/PRUNE2regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.
METHODS
The reciprocalPCA3andPRUNE2gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically-annotated cases post-radical prostatectomy: a single-institution discovery cohort (n=107) and a multi-institution validation cohort (n=497). We compared the tumor gene expression ofPCA3andPRUNE2to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.
RESULTS
We consistently observed increased expression ofPCA3and decreased expression ofPRUNE2in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels ofPCA3orPRUNE2and time to disease recurrence, independent of tumor grades and stages.
CONCLUSIONS
We concluded that upregulation of the lncRNAPCA3and targeted downregulation of the protein-codingPRUNE2gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted.
FUNDING
We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).
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