Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

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-institution discovery cohort (n=107) and a multi-institution 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).

eLife. 2023 Jan 16 [Epub ahead of print]

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

Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States., Department of Pathology, University of Utah, Salt Lake City, United States., Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Newark, United States., Department of Biochemistry, University of São Paulo, São Paulo, Brazil., Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, United States., Department of Biostatistics, University of Florida, Gainesville, United States., Department of Medicine, Baylor College of Medicine, Houston, United States., Division of Urology, University of São Paulo, São Paulo, Brazil., Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil., Laboratory of Computational Biology, A.C. Camargo Cancer Center, Sao Paulo, Brazil., MBrace Therapeutics, San Diego, United States., Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States., Department of Radiation Oncology, Rutgers, The State University of New Jersey, Newark, United States., Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Newark, United States.