Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
Richard C Lauer,
Marc Barry,
Tracey L Smith,
Andrew Maltez Thomas,
Jin Wu,
Ruofei Du,
Ji-Hyun Lee,
Arpit Rao,
Andrey S Dobroff,
Marco A Arap,
Diana N Nunes,
Israel T Silva,
Emmanuel Dias-Neto,
Isan Chen,
Dennis J McCance,
Webster K Cavenee,
Renata Pasqualini,
Wadih Arap
Affiliations
Richard C Lauer
University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States
Marc Barry
Department of Pathology, University of Utah, Salt Lake City, Utah, United States
Tracey L Smith
Rutgers Cancer Institute of New Jersey, Newark, New Jersey, United States; Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, New Jersey, United States
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
Jin Wu
University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States; Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States
Ruofei Du
Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Department of Biostatistics, University of Florida, Gainesville, Florida, United States; Division of Quantitative Sciences, University of Florida Health Cancer Center, Gainesville, Florida, United States
Arpit Rao
Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
Andrey S Dobroff
University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States; Division of Molecular Medicine, Department of Medicine, Albuquerque, United States
Marco A Arap
Division of Urology, University of São Paulo Medical School, São Paulo, Brazil; Syrian-Lebanese Hospital, São Paulo, Brazil
Diana N Nunes
Laboratory of Medical Genomics, A.C. Camargo Cancer Center, São Paulo, Brazil
Israel T Silva
Laboratory of Bioinformatics and Computational Biology, A.C. Camargo Cancer Center, São Paulo, Brazil
Emmanuel Dias-Neto
Laboratory of Medical Genomics, A.C. Camargo Cancer Center, São Paulo, Brazil
Isan Chen
MBrace Therapeutics, San Diego, California, United States
Dennis J McCance
University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, United States; Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States
Webster K Cavenee
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, United States
Renata Pasqualini
Rutgers Cancer Institute of New Jersey, Newark, New Jersey, United States; Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, New Jersey, United States
Rutgers Cancer Institute of New Jersey, Newark, New Jersey, United States; Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States
Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene 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-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to 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 of PCA3 and decreased expression of PRUNE2 in 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 of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene 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).
