The long non-coding RNA PCA3: an update of its functions and clinical applications as a biomarker in prostate cancer

Prostate cancer antigen 3 (PCA3) is an overexpressed prostate long non-coding RNA (lncRNA), transcribed from an intronic region at the long arm of human chromosome 9q21–22. It has been described that PCA3 modulates prostate cancer (PCa) cell survival through modulating androgen receptor (AR) signaling, besides controlling the expression of several androgen responsive and cancer-related genes, including epithelial–mesenchymal transition (EMT) markers and those regulating gene expression and cell signaling. Also, PCA3 urine levels have been successfully used as a PCa diagnostic biomarker. In this review, we have highlighted recent findings regarding PCA3, addressing its gene structure, putative applications as a biomarker, a proposed origin of this lncRNA, roles in PCa biology and expression patterns. We also updated data regarding PCA3 interactions with cancer-related miRNAs and expression in other tissues and diseases beyond the prostate. Altogether, literature data indicate aberrant expression and dysregulated activity of PCA3, suggesting PCA3 as a promising relevant target that should be even further evaluated on its applicability for PCa detection and management.

[1]  Joanne L Welton,et al.  Can urinary exosomes act as treatment response markers in prostate cancer? , 2009, Journal of Translational Medicine.

[2]  R. Eeles,et al.  Diversity of TMPRSS2-ERG fusion transcripts in the human prostate , 2007, Oncogene.

[3]  Seongjoon Koo,et al.  PCA3: a molecular urine assay for predicting prostate biopsy outcome. , 2008, The Journal of urology.

[4]  Liping Xie,et al.  Diagnostic performance of PCA3 and hK2 in combination with serum PSA for prostate cancer , 2018, Medicine.

[5]  W. Isaacs,et al.  DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. , 1999, Cancer research.

[6]  T. D. de Reijke,et al.  Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. , 2014, European urology.

[7]  W. Ellis,et al.  Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. , 2009, European urology.

[8]  P. Troncoso,et al.  PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. , 2008, The Journal of urology.

[9]  Zhongming Zhao,et al.  New Genomic Structure for Prostate Cancer Specific Gene PCA3 within BMCC1: Implications for Prostate Cancer Detection and Progression , 2009, PloS one.

[10]  L. Djurasić,et al.  The analysis of some factors that influence on serum PSA level in localized prostate cancer patients: mathematical model. , 2011, Acta chirurgica Iugoslavica.

[11]  M. Colombel,et al.  Comparative Evaluation of Urinary PCA3 and TMPRSS2: ERG Scores and Serum PHI in Predicting Prostate Cancer Aggressiveness , 2014, International journal of molecular sciences.

[12]  E. Klein,et al.  Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: Exploratory analysis from 12,076 patients. , 2017, Oncotarget.

[13]  Zhankui Jia,et al.  MiR-218 impedes IL-6-induced prostate cancer cell proliferation and invasion via suppression of LGR4 expression. , 2016, Oncology reports.

[14]  J. Schalken.  Validation of molecular targets in prostate cancer , 2005, BJU international.

[15]  W. Zhang,et al.  PSGR, a novel prostate-specific gene with homology to a G protein-coupled receptor, is overexpressed in prostate cancer. , 2000, Cancer research.

[16]  Adrian Preda,et al.  Prostate cancer proteomics: Current trends and future perspectives for biomarker discovery , 2017, Oncotarget.

[17]  H. Cammann,et al.  Comparative assessment of urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion with the serum [-2]proprostate-specific antigen-based prostate health index for detection of prostate cancer. , 2013, Clinical chemistry.

[18]  L. Goulart,et al.  Combined analysis of multiple mRNA markers by RT-PCR assay for prostate cancer diagnosis. , 2008, Clinical biochemistry.

[19]  Yi Zhang,et al.  The long non-coding RNA MALAT1 interacted with miR-218 modulates choriocarcinoma growth by targeting Fbxw8. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[20]  A. Bhan,et al.  Long Noncoding RNA and Cancer: A New Paradigm. , 2017, Cancer research.

[21]  J. Schalken,et al.  Preliminary evaluation of the effect of dutasteride on PCA3 in post‐DRE urine sediments: A randomized, open‐label, parallel‐group pilot study , 2009, The Prostate.

[22]  Johan Skog,et al.  Nucleic acids within urinary exosomes/microvesicles are potential biomarkers for renal disease. , 2010, Kidney International.

[23]  S. Srivastava,et al.  PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume. , 2008, The Journal of urology.

[24]  Lu Yu,et al.  PCA3 and TMPRSS2-ERG gene fusions as diagnostic biomarkers for prostate cancer. , 2016, Chinese journal of cancer research = Chung-kuo yen cheng yen chiu.

[25]  Mesut Remzi,et al.  Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. , 2008, European urology.

[26]  J. Futterer,et al.  Value of PCA3 to Predict Biopsy Outcome and Its Potential Role in Selecting Patients for Multiparametric MRI , 2013, International journal of molecular sciences.

[27]  J. Witjes,et al.  Detailed analysis of histopathological parameters in radical prostatectomy specimens and PCA3 urine test results , 2008, The Prostate.

[28]  J. Mellon,et al.  Defining prostate cancer risk before prostate biopsy. , 2013, Urologic oncology.

[29]  L. Salomon,et al.  Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance. , 2011, European urology.

[30]  E. Colás,et al.  A Three‐Gene panel on urine increases PSA specificity in the detection of prostate cancer , 2011, The Prostate.

[31]  X. Puig,et al.  Correlation of mRNA-PCA3 urine levels with the new grading system in prostate cancer. , 2019, Revista espanola de patologia : publicacion oficial de la Sociedad Espanola de Anatomia Patologica y de la Sociedad Espanola de Citologia.

[32]  Mesut Remzi,et al.  The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance , 2012, BJU international.

[33]  J. Crowley,et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. , 2004, The New England journal of medicine.

[34]  Howard Y. Chang,et al.  Gene regulation: Long RNAs wire up cancer growth , 2013, Nature.

[35]  G. Morgia,et al.  PHI and PCA3 improve the prognostic performance of PRIAS and Epstein criteria in predicting insignificant prostate cancer in men eligible for active surveillance , 2016, World Journal of Urology.

[36]  A. Giannantoni,et al.  The combination of urine DD3PCA3 mRNA and PSA mRNA as molecular markers of prostate cancer , 2009, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[37]  Ana Emília Goulart Lemos,et al.  PCA3 long noncoding RNA modulates the expression of key cancer-related genes in LNCaP prostate cancer cells , 2016, Tumor Biology.

[38]  G. Andriole,et al.  PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. , 2010, The Journal of urology.

[39]  J. Schalken,et al.  Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. , 2012, The Journal of urology.

[40]  T. Katagiri,et al.  Cancer Diagnosis , 1992, Springer Berlin Heidelberg.

[41]  R. Sidman,et al.  Going viral? Linking the etiology of human prostate cancer to the PCA3 long noncoding RNA and oncogenic viruses , 2017, EMBO molecular medicine.

[42]  A. Ruffion,et al.  Additional value of PCA3 density to predict initial prostate biopsy outcome , 2014, World Journal of Urology.

[43]  Wei Wei,et al.  High PCA3 scores in urine correlate with poor-prognosis factors in prostate cancer patients. , 2015, International journal of clinical and experimental medicine.

[44]  M. Truong,et al.  Toward the detection of prostate cancer in urine: a critical analysis. , 2013, The Journal of urology.

[45]  A. Ruffion,et al.  PCA3 and PCA3-Based Nomograms Improve Diagnostic Accuracy in Patients Undergoing First Prostate Biopsy , 2013, International journal of molecular sciences.

[46]  S. Taneja.  Re: Association between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. , 2017, The Journal of urology.

[47]  M. Caetano,et al.  PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling , 2012, BMC Cancer.

[48]  Yair Lotan,et al.  Systematic review of complications of prostate biopsy. , 2013, European urology.

[49]  Zhicai Zhang,et al.  Improved sensitivity and specificity for prostate cancer diagnosis based on the urine PCA3/PSA ratio acquired by sequence‑specific RNA capture. , 2015, Oncology reports.

[50]  Z. Hall.  Cancer , 1906, The Hospital.

[51]  Kotb Abdelmohsen,et al.  Noncoding RNAs in Alzheimer's disease , 2018, Wiley interdisciplinary reviews. RNA.

[52]  Amy Blase,et al.  PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. , 2007, Urology.

[53]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[54]  J. Schalken,et al.  New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene. , 2003, Urology.

[55]  R. Rocha,et al.  Prostate-specific RNA aptamer: promising nucleic acid antibody-like cancer detection , 2015, Scientific Reports.

[56]  Chaochun Liu,et al.  The imprinted H19 lncRNA antagonizes let-7 microRNAs. , 2013, Molecular cell.

[57]  L. Marks,et al.  APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. , 2006, Clinical chemistry.

[58]  M. Cooperberg,et al.  Utility of PCA3 in patients undergoing repeat biopsy for prostate cancer , 2011, Prostate Cancer and Prostatic Diseases.

[59]  Y. Allory,et al.  The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy , 2012, BJU international.

[60]  J. Schalken,et al.  Evaluation of urinary prostate cancer antigen‐3 (PCA3) and TMPRSS2‐ERG score changes when starting androgen‐deprivation therapy with triptorelin 6‐month formulation in patients with locally advanced and metastatic prostate cancer , 2014, BJU international.

[61]  Juntang Lin,et al.  Long noncoding RNA PCA3 regulates prostate cancer through sponging miR‐218‐5p and modulating high mobility group box 1 , 2019, Journal of cellular physiology.

[62]  P. Sednaoui,et al.  Chronic prostatitis does not influence urinary PCA3 score , 2012, The Prostate.

[63]  G. Cigliana,et al.  PCA3 in prostate cancer and tumor aggressiveness detection on 407 high-risk patients: a National Cancer Institute experience , 2015, Journal of Experimental & Clinical Cancer Research.

[64]  John T. Wei,et al.  Assessment of long‐term outcomes associated with urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion at repeat biopsy , 2015, Cancer.

[65]  Annette Fenner.  Prostate cancer: PCA3 as a Grade Reclassification Predictor , 2017, Nature Reviews Urology.

[66]  E. Wagar,et al.  Combination of Prostate Cancer Antigen 3 and Prostate-Specific Antigen Improves Diagnostic Accuracy in Men at Risk of Prostate Cancer. , 2018, Archives of pathology & laboratory medicine.

[67]  U. Gezer,et al.  PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade. , 2017, Anticancer research.

[68]  A. Partin,et al.  Accuracy of PCA3 measurement in predicting short-term biopsy progression in an active surveillance program. , 2010, The Journal of urology.

[69]  Z. Zong,et al.  The role of long non-coding RNA PCA3 in epithelial ovarian carcinoma tumorigenesis and progression. , 2017, Gene.

[70]  L. Lacombe,et al.  Prognostic value of urinary prostate cancer antigen 3 (PCA3) during active surveillance of patients with low‐risk prostate cancer receiving 5α‐reductase inhibitors , 2018, BJU international.

[71]  D. Bruzzese,et al.  Improving the prediction of pathologic outcomes in patients undergoing radical prostatectomy: the value of prostate cancer antigen 3 (PCA3), prostate health index (phi) and sarcosine. , 2015, Anticancer research.

[72]  Y. Gui,et al.  Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease , 2015, Oncotarget.

[73]  A. Veltri,et al.  In‐parallel comparative evaluation between multiparametric magnetic resonance imaging, prostate cancer antigen 3 and the prostate health index in predicting pathologically confirmed significant prostate cancer in men eligible for active surveillance , 2016, BJU international.

[74]  Z. Bian,et al.  Long non-coding RNA CCAT1 promotes human retinoblastoma SO-RB50 and Y79 cells through negative regulation of miR-218-5p. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[75]  James T. Lin,et al.  Urine Exosomes for Non-Invasive Assessment of Gene Expression and Mutations of Prostate Cancer , 2016, PloS one.

[76]  Peng Guo,et al.  Tumor-suppressive microRNA-218 inhibits tumor angiogenesis via targeting the mTOR component RICTOR in prostate cancer , 2016, Oncotarget.

[77]  J. Witjes,et al.  Predictive value of PCA3 in urinary sediments in determining clinico‐pathological characteristics of prostate cancer , 2010, The Prostate.

[78]  Zev N. Kronenberg,et al.  Transposable Elements Are Major Contributors to the Origin, Diversification, and Regulation of Vertebrate Long Noncoding RNAs , 2013, PLoS genetics.

[79]  A. Haese*,et al.  The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free‐to‐total prostate‐specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies? , 2010, BJU international.

[80]  J. Schalken,et al.  Differential expression of PCA3 and its overlapping PRUNE2 transcript in prostate cancer , 2010, The Prostate.

[81]  R. Dahiya,et al.  Interaction and cross ‐ talk between non ‐ coding RNAs , 2017 .

[82]  A. Haese*,et al.  Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. , 2011, European urology.

[83]  N. Seki,et al.  Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer , 2014, Cancer science.

[84]  R. Sidman,et al.  PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3 , 2015, Proceedings of the National Academy of Sciences.

[85]  M. Colombel,et al.  Urinary PCA3 score predicts prostate cancer multifocality. , 2011, The Journal of urology.

[86]  Jonathan I. Epstein,et al.  Longitudinal Assessment of Urinary PCA3 for Predicting Prostate Cancer Grade Reclassification in Favorable Risk Men during Active Surveillance , 2017, Prostate Cancer and Prostatic Diseases.

[87]  R. V. D. van den Bergh,et al.  Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. , 2010, European urology.

[88]  T. Mayer,et al.  Nanoresonator chip-based RNA sensor strategy for detection of circulating tumor cells: response using PCA3 as a prostate cancer marker. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[89]  Zeping Han,et al.  Snail-activated long non-coding RNA PCA3 up-regulates PRKD3 expression by miR-1261 sponging, thereby promotes invasion and migration of prostate cancer cells , 2016, Tumor Biology.

[90]  R. Coda,et al.  Histological chronic prostatitis and high‐grade prostate intra‐epithelial neoplasia do not influence urinary prostate cancer gene 3 score , 2012, BJU international.

[91]  G. Beaudry,et al.  Identification of PCA3 (DD3) in prostatic carcinoma by in situ hybridization , 2007, Modern Pathology.

[92]  Melissa J. Fullwood,et al.  Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer , 2016, Genom. Proteom. Bioinform..

[93]  Walter N. Moss,et al.  New Noncoding Lytic Transcripts Derived from the Epstein-Barr Virus Latency Origin of Replication, oriP, Are Hyperedited, Bind the Paraspeckle Protein, NONO/p54nrb, and Support Viral Lytic Transcription , 2015, Journal of Virology.

[94]  J. Fracchia,et al.  PCA3 permutation increases the prostate biopsy yield , 2012 .

[95]  J. Schalken,et al.  Rational basis for the combination of PCA3 and TMPRSS2:ERG gene fusion for prostate cancer diagnosis , 2013, The Prostate.

[96]  M. Babjuk,et al.  Differential display code 3 (DD3/PCA3) in prostate cancer diagnosis. , 2010, Anticancer research.