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

University of New Mexico, United States
University of Utah, United States
Rutgers, The State University of New Jersey, United States
University of São Paulo, Brazil
University of Arkansas for Medical Sciences, United States
University of Florida, United States
Baylor College of Medicine, United States
University of São Paulo, Brazil
AC Camargo Cancer Center, Brazil
A.C. Camargo Cancer Center, Brazil
MBrace Therapeutics, United States
University of California, San Diego, United States
Rutgers Cancer Institute of New Jersey, United States

Jan 16, 2023

https://doi.org/10.7554/eLife.81929

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Abstract
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Abstract

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).

Data availability

For the discovery cohort, all data generated or analyzed are included in the manuscript and source data files, except for patient-level ethnicity data. Patient-level ethnicity data is not included due to the potential for identifiability. However detailed summary ethnicity data is presented in the manuscript and in Table 1. Requests to access the patient level ethnicity data should be directed to the corresponding author with a project proposal. Source codes are also available in the supplemental source code file. For the Validation Cohort, clinicopathological patient characteristics and gene level transcription data from The Cancer Genome Atlas (TCGA) were accessed from the UCSC Xena Resource.

The following previously published data sets were used

1. University of North Carolina TCGA genome characterization center
(2017) TCGA prostate adenocarcinoma (PRAD) gene expression by RNAseq (polyA+ IlluminaHiSeq)
TCGA Prostate Cancer (PRAD) TCGA.PRAD.sampleMap/HiSeqV2.

https://xenabrowser.net/datapages/?dataset=TCGA.PRAD.sampleMap%2FHiSeqV2&host=https%3A%2F%2Ftcga.xenahubs.net&removeHub=https%3A%2F%2Fxena.treehouse.gi.ucsc.edu%3A443

Article and author information

Author details

Richard C Lauer

Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States

Competing interests
No competing interests declared.
Marc Barry

Department of Pathology, University of Utah, Salt Lake City, United States

Competing interests
No competing interests declared.
Tracey L Smith

Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Newark, United States

Competing interests
No competing interests declared.
Andrew Maltez Thomas

Department of Biochemistry, University of São Paulo, São Paulo, Brazil

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5789-3354
Jin Wu

Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States

Competing interests
No competing interests declared.
Ruofei Du

Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, United States

Competing interests
No competing interests declared.
Ji-Hyun Lee

Department of Biostatistics, University of Florida, Gainesville, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6420-5150
Arpit Rao

Department of Medicine, Baylor College of Medicine, Houston, United States

Competing interests
No competing interests declared.
Andrey S Dobroff

Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States

Competing interests
No competing interests declared.
Marco A Arap

Division of Urology, University of São Paulo, São Paulo, Brazil

Competing interests
No competing interests declared.
Diana N Nunes

Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil

Competing interests
Diana N Nunes, The University of New Mexico filed patent applications on PRUNE2- related technology, for which Diana Nunes was an inventor (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. No payments were made to Diana Nunes, and the author has no other competing interests to declare..
Israel T Silva

Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil

Competing interests
No competing interests declared.
Emmanuel Dias-Neto

Laboratory of Computational Biology, A.C. Camargo Cancer Center, Sao Paulo, Brazil

Competing interests
Emmanuel Dias-Neto, The University of New Mexico filed patent applications on PRUNE2- related technology, for which Emmanuel Dias-Neto was an inventor (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreement terminated. No payments were made to Emmanuel Dias-Neto, and the author has no other competing interests to declare..
Isan Chen

MBrace Therapeutics, San Diego, United States

Competing interests
Isan Chen, serves as the Chief Executive Officer of MBrace Therapeutics. Mbrace did not provide financial support for the present work..
Dennis J McCance

Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States

Competing interests
No competing interests declared.
Webster K Cavenee

Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States

Competing interests
Webster K Cavenee, is a founder and shareholder of Interleukin Combinatorial Therapies, Inc., InVaMet, Inc., and io9, LLC; none of these companies provided funds or participated in the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institution. The author received support for attending the Aspen Cancer Conference, and participated in a Leadership or fiduciary role. The author holds a Leadership or fiduciary role at Genetron Health for which they receive board fees, and are on the Board of Directors for the GBM AGILE Clinical Trial. The author has no other competing interests to declare..
Renata Pasqualini

Department of Radiation Oncology, Rutgers, The State University of New Jersey, Newark, United States

Competing interests
Renata Pasqualini, Reviewing editor, eLifeThe University of New Mexico filed patent applications on PRUNE2- related technology (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. RP (and WA) is a founder and equity stockholder of PhageNova Bio, Inc. and of MBrace Therapeutics, Inc.; RP also serves as a paid consultant and the Chief Scientific Officer of PhageNova Bio and as a paid consultant and member of the Board of Directors for MBrace Therapeutics. Mbrace did not provide financial support for the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institutions..
Wadih Arap

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Newark, United States

For correspondence
wa116@newark.rutgers.edu

Competing interests
Wadih Arap, Reviewing editor, eLifeThe University of New Mexico filed patent applications on PRUNE2-related technology (inventors: DNN, EDN, RP, and WA). Those applications were briefly optioned by MBrace Therapeutics, but the applications have since been abandoned and the agreements terminated. WA is a founder and equity stockholder of PhageNova Bio, Inc. and of MBrace Therapeutics, Inc. Mbrace did not provide financial support for the present work. These arrangements are managed in accordance with the established institutional conflict of interest policies for the respective institutions..

"This ORCID iD identifies the author of this article:" 0000-0002-8686-4584

Funding

National Cancer Institute (P30CA118100)

Richard C Lauer

National Cancer Institute (P30CA072720)

Renata Pasqualini
Wadih Arap

Levy-Longenbaugh Donor-Advised Fund

Renata Pasqualini
Wadih Arap

Prostate Cancer Foundation

Renata Pasqualini
Wadih Arap

Brazilian National Council for Scientific and Technological Development

Emmanuel Dias-Neto

Associação Beneficente Alzira Denise Hertzog Silva

Emmanuel Dias-Neto

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: For the discovery cohort, there was University of New Mexico Health Sciences Institutional Review Board (IRB) approval (HRRC15-138), and the study was carried out in accordance with the United States Common Rule. As the discovery cohort involved secondary use of archival biospecimens, the IRB waived the requirement for informed consent .

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.