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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eLife assessment
Upregulation of PCA3 and downregulation of PRUNE2 in prostate cancer were first discovered in this work, which innovatively demonstrated that PCA3 and PRUNE3 function as an oncogene and a tumor suppressor gene respectively. The conclusion is further enhanced by the use of two distinct patient cohorts, which highlights the clinical significance. Functional experiments will be needed to more comprehensively validate the findings.
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Abstract
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).
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eLife assessment
Upregulation of PCA3 and downregulation of PRUNE2 in prostate cancer were first discovered in this work, which innovatively demonstrated that PCA3 and PRUNE3 function as an oncogene and a tumor suppressor gene respectively. The conclusion is further enhanced by the use of two distinct patient cohorts, which highlights the clinical significance. Functional experiments will be needed to more comprehensively validate the findings.
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Reviewer #1 (Public Review):
Prostate cancer is the most common cancer and the second most common cause of cancer death in men. Hence, there continues to be a pressing need for new diagnostic and therapeutic approaches for this disease, as well as better prognostic biomarkers to guide treatment. In this manuscript, Lauer et al. show increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. And there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence. These findings suggest a role for PCA3 and PRUNE2 in prostate cancer. And most conclusions of this paper are supported by data.
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Reviewer #2 (Public Review):
The purpose of this paper is to consider the utility of the long non-coding RNA PCA3, along with the gene PCA3 in the diagnosis of human prostate cancer. The study extends earlier findings by this group that the PRUNE2 gene product may function as a prostate tumor suppressor. The study employed two separate patient cohorts: one of 107 patients from the University of New Mexico Comprehensive Cancer Center, with organ-confined prostate cancer at their original diagnosis, and one of 497 patients with organ-confined prostate cancer from The Cancer Genome Atlas (TCGA). The authors report an overall increase in PCA levels along with a general decrease in PRUNE2 gene expression. The authors conclude that PRUNE2 functions as a prostate tumor suppressor whose levels negatively correlate with PCA3 levels. They further …
Reviewer #2 (Public Review):
The purpose of this paper is to consider the utility of the long non-coding RNA PCA3, along with the gene PCA3 in the diagnosis of human prostate cancer. The study extends earlier findings by this group that the PRUNE2 gene product may function as a prostate tumor suppressor. The study employed two separate patient cohorts: one of 107 patients from the University of New Mexico Comprehensive Cancer Center, with organ-confined prostate cancer at their original diagnosis, and one of 497 patients with organ-confined prostate cancer from The Cancer Genome Atlas (TCGA). The authors report an overall increase in PCA levels along with a general decrease in PRUNE2 gene expression. The authors conclude that PRUNE2 functions as a prostate tumor suppressor whose levels negatively correlate with PCA3 levels. They further surmise that PCA3 in turn functions as a dominant-negative oncogene. Consequently, they expect that loss of increased PCA3 levels can lead to loss of PRUNE2 and increased prostate cancer tumor formation.
One interesting observation, consistent with earlier studies, is that PCA3 levels are highest in low-grade tumors, and then decrease as the tumors progress to a higher stage and grade. This suggests that increased PCA3 may be important for early tumor formation while possibly impeding tumor progression. The decreased PCA3 levels seen in later prostate cancer may, the authors hypothesize, be related to alterations in androgen receptor (AR) function in these higher-grade cancers. Thus, while the presence of PCA3 may be an early marker of prostate cancer formation, the results indicate that its presence in early cancers is not, by itself, predictive of future patient outcomes, as tumor progression may actually depend on the later decrease in PCA3 levels.
A strength of this study is the use of two non-redundant patient cohorts to thoroughly analyze the consequence of alterations in PRUNE2 and PCA3 by directly analyzing analyte levels in human tissue samples. The study provides important data supporting the occurrence of a loss of PRUNE2 and gain of PCA3 in organ-confined prostate cancer. The principal takeaway from this report is to highlight the role of the PRUNE2/PCA3 axis in early prostate cancer and to encourage the use of PCA3 antagonists in the prevention and treatment of early prostate cancer. It is unlikely that examination of tissue samples for alterations in PRUNE2 or PCA3 levels will be useful in prostate cancer diagnosis or prognosis as the data do not suggest that these changes in early cancers are predictive of future outcomes. It may be, however, that longitudinal analysis of PCA3 levels in patient plasma or circulating tumor cells could be a useful adjunct to follow the course of tumor progression.
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Reviewer #3 (Public Review):
In this manuscript, the authors found upregulation of PCA3 and downregulation of PRUNE2 in prostate cancer as compared with normal prostate in two retrospective and independent patient cohorts, supporting that PCA3 and PRUNE3 function as an oncogene and a tumor suppressor gene, respectively. The findings presented here represent additional evidence for the functional reciprocal co-regulation of PCA3 and PRUNE2 in the setting of early tumorigenesis but not in late events in human prostate cancer. But further studies of PCA3/PRUNE2 dysregulation are still needed.
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