1. Medicine

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

  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap  Is a corresponding author
  1. University of New Mexico, United States
  2. University of Utah, United States
  3. Rutgers, The State University of New Jersey, United States
  4. University of São Paulo, Brazil
  5. University of Arkansas for Medical Sciences, United States
  6. University of Florida, United States
  7. Baylor College of Medicine, United States
  8. University of São Paulo, Brazil
  9. AC Camargo Cancer Center, Brazil
  10. A.C. Camargo Cancer Center, Brazil
  11. MBrace Therapeutics, United States
  12. University of California, San Diego, United States
  13. Rutgers Cancer Institute of New Jersey, United States
https://doi.org/10.7554/eLife.81929
Share this article
Cite this article
  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap
(2023)
Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
eLife 12:e81929.
https://doi.org/10.7554/eLife.81929
  2. Download BibTeX
  3. Download .RIS

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

Article and author information

Author details

  1. Richard C Lauer

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  2. Marc Barry

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.

  3. Tracey L Smith

    Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    No competing interests declared.

  4. Andrew Maltez Thomas

    Department of Biochemistry, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5789-3354

  5. Jin Wu

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  6. Ruofei Du

    Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, United States
    Competing interests
    No competing interests declared.

  7. Ji-Hyun Lee

    Department of Biostatistics, University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6420-5150

  8. Arpit Rao

    Department of Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  9. Andrey S Dobroff

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  10. Marco A Arap

    Division of Urology, University of São Paulo, São Paulo, Brazil
    Competing interests
    No competing interests declared.

  11. 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..

  12. Israel T Silva

    Laboratory of Computational Biology, AC Camargo Cancer Center, Sao Paulo, Brazil
    Competing interests
    No competing interests declared.

  13. 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..

  14. 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..

  15. Dennis J McCance

    Comprehensive Cancer Center, University of New Mexico, Albuquerque, United States
    Competing interests
    No competing interests declared.

  16. 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..

  17. 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..

  18. 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..
    ORCID icon "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

© 2023, Lauer et al.

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.

Metrics

  • 670
    views
  • 121
    downloads
  • 2
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Richard C Lauer
  2. Marc Barry
  3. Tracey L Smith
  4. Andrew Maltez Thomas
  5. Jin Wu
  6. Ruofei Du
  7. Ji-Hyun Lee
  8. Arpit Rao
  9. Andrey S Dobroff
  10. Marco A Arap
  11. Diana N Nunes
  12. Israel T Silva
  13. Emmanuel Dias-Neto
  14. Isan Chen
  15. Dennis J McCance
  16. Webster K Cavenee
  17. Renata Pasqualini
  18. Wadih Arap
(2023)
Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
eLife 12:e81929.
https://doi.org/10.7554/eLife.81929

Share this article

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

Categories and tags

Research organism

Further reading

    1. Immunology and Inflammation
    2. Medicine

    Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns

    Ole Bæk, Tik Muk ... Duc Ninh Nguyen
    Research Article

    Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver-derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.

    1. Medicine
    2. Microbiology and Infectious Disease

    Differences in HIV-1 reservoir size, landscape characteristics, and decay dynamics in acute and chronic treated HIV-1 Clade C infection

    Kavidha Reddy, Guinevere Q Lee ... Thumbi Ndung'u
    Research Article

    Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are a barrier to cure efforts. Early antiretroviral therapy (ART) enables post-treatment viral control in some cases, but mechanisms remain unclear. We hypothesised that ART initiated before peak viremia impacts HIV-1 subtype C reservoirs. We studied 35 women at high risk of infection from Durban, South Africa, identified with hyperacute HIV by twice-weekly HIV-RNA testing. Participants included 11 starting ART at a median of 456 (297–1203) days post-onset of viremia (DPOV) and 24 at 1 (1–3) DPOV. Peripheral blood mononuclear cells (PBMCs) were used to measured total HIV-1 DNA by droplet digital PCR (ddPCR) and sequence viral reservoir genomes by full-length proviral sequencing (FLIP-seq). ART during hyperacute infection blunted peak viremia (p<0.0001), but contemporaneous total HIV-1 DNA did not differ (p=0.104). Over 1 year, a decline of total HIV-1 DNA was observed in early treated persons (p=0.0004), but not late treated. Among 697 viral genome sequences, the proviral genetic landscape differed between untreated, late treated, and early treated groups. Intact genomes after 1 year were higher in untreated (31%) versus late treated (14%) and early treated (0%). Treatment in both late and early infection caused more rapid decay of intact (13% and 51% per month) versus defective (2% and 35%) viral genomes. However, intact genomes persisted 1 year post chronic treatment but were undetectable with early ART. Early ART also reduced phylogenetic diversity of intact genomes and limited cytotoxic T lymphocyte immune escape variants in the reservoir. Overall, ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding but was associated with rapid intact viral genome decay, reduced genetic complexity, and limited immune escape, which may accelerate reservoir clearance in combination with other interventional strategies.

    1. Cancer Biology
    2. Medicine

    Development and assessment of a sustainable PhD internship program supporting diverse biomedical career outcomes

    Patrick Brandt, Dawayne Whittington ... Rebekah L Layton
    Research Article

    A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.