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Lauer, Richard C; Barry, Marc; Smith, Tracey L; Thomas, Andrew Maltez; Wu, Jin; Du, Ruofei; Lee, Ji-Hyun; Rao, Arpit; Dobroff, Andrey S; Arap, Marco A; Nunes, Diana N; Silva, Israel T; Dias-Neto, Emmanuel; Chen, Isan; McCance, Dennis J; Cavenee, Webster K; Pasqualini, Renata; Arap, Wadih

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

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  • Medientyp: E-Artikel
  • Titel: Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts
  • Beteiligte: Lauer, Richard C; Barry, Marc; Smith, Tracey L; Thomas, Andrew Maltez; Wu, Jin; Du, Ruofei; Lee, Ji-Hyun; Rao, Arpit; Dobroff, Andrey S; Arap, Marco A; Nunes, Diana N; Silva, Israel T; Dias-Neto, Emmanuel; Chen, Isan; McCance, Dennis J; Cavenee, Webster K; Pasqualini, Renata; Arap, Wadih
  • Erschienen: eLife Sciences Publications, Ltd, 2023
  • Erschienen in: eLife
  • Sprache: Englisch
  • DOI: 10.7554/elife.81929
  • ISSN: 2050-084X
  • Schlagwörter: General Immunology and Microbiology ; General Biochemistry, Genetics and Molecular Biology ; General Medicine ; General Neuroscience
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec id="abs1"><jats:title>Background:</jats:title><jats:p>We have previously shown that the long non-coding (lnc)RNA <jats:italic>prostate cancer associated 3</jats:italic> (<jats:italic>PCA3</jats:italic>; formerly <jats:italic>prostate cancer antigen 3</jats:italic>) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene <jats:italic>PRUNE2</jats:italic> (a homolog of the <jats:italic>Drosophila prune</jats:italic> gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the <jats:italic>PCA3</jats:italic>/<jats:italic>PRUNE2</jats:italic> regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.</jats:p></jats:sec><jats:sec id="abs2"><jats:title>Methods:</jats:title><jats:p>The reciprocal <jats:italic>PCA3</jats:italic> and <jats:italic>PRUNE2</jats:italic> 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 <jats:italic>PCA3</jats:italic> and <jats:italic>PRUNE2</jats:italic> to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.</jats:p></jats:sec><jats:sec id="abs3"><jats:title>Results:</jats:title><jats:p>We consistently observed increased expression of <jats:italic>PCA3</jats:italic> and decreased expression of <jats:italic>PRUNE2</jats:italic> 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 <jats:italic>PCA3</jats:italic> or <jats:italic>PRUNE2</jats:italic> and time to disease recurrence, independent of tumor grades and stages.</jats:p></jats:sec><jats:sec id="abs4"><jats:title>Conclusions:</jats:title><jats:p>We concluded that upregulation of the lncRNA <jats:italic>PCA3</jats:italic> and targeted downregulation of the protein-coding <jats:italic>PRUNE2</jats:italic> 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.</jats:p></jats:sec><jats:sec id="abs5"><jats:title>Funding:</jats:title><jats:p>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).</jats:p></jats:sec>
  • Zugangsstatus: Freier Zugang