BACKGROUND: Prostate cancer (PCa) is a heterogeneous malignancy with high variability in clinical course. Insufficient stratification according to the aggressiveness at the time of diagnosis causes unnecessary or delayed treatment. Current stratification systems are not effective enough because they are based on clinical, surgical or biochemical parameters, but do not take into account molecular factors driving PCa cancerogenesis. MicroRNAs (miRNAs) are important players in molecular pathogenesis of PCa and could serve as valuable biomarkers for the assessment of disease aggressiveness and its prognosis. METHODS: In the study, in total, 280 PCa patients were enrolled. The miRNA expression profiles were analyzed in FFPE PCa tissue using the miRCURY LNA miRNA PCR System. The expression levels of candidate miRNAs were further verified by two-level validation using the RT-qPCR method and evaluated in relation to PCa stratification reflecting the disease aggressiveness. RESULTS: MiRNA profiling revealed 172 miRNAs dysregulated between aggressive (ISUP 3-5) and indolent PCa (ISUP 1) (p < 0.05). In the training and validation cohort, miR-15b-5p and miR-106b-5p were confirmed to be significantly upregulated in tissue of aggressive PCa when their level was associated with disease aggressiveness. Furthermore, we established a prognostic score combining the level of miR-15b-5p and miR-106b-5p with serum PSA level, which discriminated indolent PCa from an aggressive form with even higher analytical parameters (AUC being 0.9338 in the training set and 0.8014 in the validation set, respectively). The score was also associated with 5-year biochemical progression-free survival (bPFS) of PCa patients. CONCLUSIONS: We identified a miRNA expression pattern associated with disease aggressiveness in prostate cancer patients. These miRNAs may be of biological interest as the focus can be also set on their specific role within the molecular pathology and the molecular mechanism that underlies the aggressivity of prostate cancer.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Internal Medicine Division of Oncology Medical University of Graz Graz Austria

Department of Oncological Pathology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Urologic Oncology Clinic of Surgical Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

See more in PubMed

Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

Parker C, Castro E, Fizazi K, et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-1134.

Carter HB. Management of low (favourable)-risk prostate cancer: management of low-risk (favourable) prostate cancer. BJU Int. 2011;108(11):1684-1695.

Toktas G, Demiray M, Erkan E, Kocaaslan R, Yucetas U, Unluer SE. The effect of antibiotherapy on prostate-specific antigen levels and prostate biopsy results in patients with levels 2.5 to 10 ng/mL. J Endourol. 2013;27(8):1061-1067.

Murphy K, Murphy BT, Boyce S, et al. Integrating biomarkers across omic platforms: an approach to improve stratification of patients with indolent and aggressive prostate cancer. Mol Oncol. 2018;12(9):1513-1525.

Rodrigues G, Warde P, Pickles T, et al. Pre-treatment risk stratification of prostate cancer patients: a critical review. Can Urol Assoc J. 2012;6(2):121-127.

O'Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol. 2018;9:402.

Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834-838.

Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TLJ, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67(13):6130-6135.

Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103(7):2257-2261.

Fabris L, Ceder Y, Chinnaiyan AM, et al. The potential of microRNAs as prostate cancer biomarkers. Eur Urol. 2016;70(2):312-322.

Wang L, Tang H, Thayanithy V, et al. Gene networks and microRNAs implicated in aggressive prostate cancer. Cancer Res. 2009;69(24):9490-9497.

Spahn M, Kneitz S, Scholz CJ, et al. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer. 2010;127(2):394-403.

Richardsen E, Andersen S, Melbø-Jørgensen C, et al. MicroRNA 141 is associated to outcome and aggressive tumor characteristics in prostate cancer. Sci Rep. 2019;9(1):386.

Xi Y, Nakajima G, Gavin E, et al. Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. RNA. 2007;13(10):1668-1674.

Buhmeida A, Pyrhönen S, Laato M, Collan Y. Prognostic factors in prostate cancer. Diagn Pathol. 2006;1:4.

Vanacore D, Boccellino M, Rossetti S, et al. Micrornas in prostate cancer: an overview. Oncotarget. 2017;8(30):50240-50251.

Ambs S, Prueitt RL, Yi M, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 2008;68(15):6162-6170.

Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27(12):1788-1793.

Larne O, Martens-Uzunova E, Hagman Z, et al. miQ-a novel microRNA based diagnostic and prognostic tool for prostate cancer. Int J Cancer. 2013;132(12):2867-2875.

Martens-Uzunova ES, Jalava SE, Dits NF, et al. Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene. 2012;31(8):978-991.

Avgeris M, Stravodimos K, Fragoulis EG, Scorilas A. The loss of the tumour-suppressor miR-145 results in the shorter disease-free survival of prostate cancer patients. Br J Cancer. 2013;108(12):2573-2581.

Schaefer A, Jung M, Mollenkopf HJ, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 2010;126(5):1166-1176.

Karatas OF, Guzel E, Suer I, et al. miR-1 and miR-133b are differentially expressed in patients with recurrent prostate cancer. PLoS One. 2014;9(6):e98675.

Li T, Li RS, Li YH, et al. miR-21 as an independent biochemical recurrence predictor and potential therapeutic target for prostate cancer. J Urol. 2012;187(4):1466-1472.

Wagner S, Ngezahayo A, Murua Escobar H, Nolte I. Role of miRNA let-7 and its major targets in prostate cancer. BioMed Res Int. 2014;2014:1-14.

Hudson RS, Yi M, Esposito D, et al. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene. 2013;32(35):4139-4147.

Zhang X, Jin K, Luo JD, Liu B, Xie LP. MicroRNA-107 inhibits proliferation of prostate cancer cells by targeting cyclin E1. Neoplasma. 2019;66(5):704-716.

Ge J, Mao L, Xu W, et al. miR-103a-3p suppresses cell proliferation and invasion by targeting tumor protein D52 in prostate cancer. J Invest Surg. 2021;34(9):984-992.

Liu ZJ, Liu SH, Li JR, Bie XC, Zhou Y. MiR-15b-5b regulates the proliferation of prostate cancer PC-3 cells via targeting LATS2. Cancer Manag Res. 2020;12:10669-10678.

Liu JJ, Zhang X, Wu XH. miR-93 promotes the growth and invasion of prostate cancer by upregulating its target genes TGFBR2, ITGB8, and LATS2. Mol Ther Oncolytics. 2018;11:14-19.

Murata T, Takayama K, Katayama S, et al. miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression. Prostate Cancer Prostatic Dis. 2010;13(4):356-361.

Said R, Garcia-Mayea Y, Trabelsi N, et al. Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in prostate cancer Tunisian patients. Mol Biol Rep. 2018;45(6):2345-2358.

Rana S, Valbuena GN, Curry E, Bevan CL, Keun HC. MicroRNAs as biomarkers for prostate cancer prognosis: a systematic review and a systematic reanalysis of public data. Br J Cancer. 2022;126(3):502-513.

Bıçaklıoğlu F, Aydın HR, Güçtaş AÖ, Aksoy HZ. The predictive ability of prostate-specific antigen (PSA) density and free/total PSA ratio in diagnosing clinically significant prostate cancer (PCa) in patients with histologically confirmed PCa with a PSA level of 2.5-10 Ng/ML. Bull Urooncol. 2021;20:215-218.

Oto J, Fernández-Pardo Á, Royo M, et al. A predictive model for prostate cancer incorporating PSA molecular forms and age. Sci Rep. 2020;10(1):2463.

Yusim I, Krenawi M, Mazor E, Novack V, Mabjeesh NJ. The use of prostate specific antigen density to predict clinically significant prostate cancer. Sci Rep. 2020;10(1):20015.

Fredsøe J, Rasmussen AKI, Mouritzen P, et al. Profiling of circulating microRNAs in prostate cancer reveals diagnostic biomarker potential. Diagnostics. 2020;10(4):188.

Liu RSC, Olkhov-Mitsel E, Jeyapala R, et al. Assessment of serum microRNA biomarkers to predict reclassification of prostate cancer in patients on active surveillance. J Urol. 2018;199(6):1475-1481.

Mello-Grand M, Gregnanin I, Sacchetto L, et al. Circulating microRNAs combined with PSA for accurate and non-invasive prostate cancer detection. Carcinogenesis. 2019;40(2):246-253.

Zidan HE, Abdul-Maksoud RS, Elsayed WSH, Desoky EAM. Diagnostic and prognostic value of serum miR-15a and miR-16-1 expression among Egyptian patients with prostate cancer. IUBMB Life. 2018;70(5):437-444.

Wang H, Peng R, Wang J, Qin Z, Xue L. Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin Epigenetics. 2018;10:59.

Feng S, Qian X, Li H, Zhang X. Combinations of elevated tissue miRNA-17-92 cluster expression and serum prostate-specific antigen as potential diagnostic biomarkers for prostate cancer. Oncol Lett. 2017;14(6):6943-6949.

Hao Y, Zhao Y, Zhao X, et al. Improvement of prostate cancer detection by integrating the PSA test with miRNA expression profiling. Cancer Invest. 2011;29(4):318-324.

Chen R, Sheng L, Zhang HJ, Ji M, Qian WQ. miR-15b-5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer. J Cell Mol Med. 2018;22(3):1855-1863.

Li M, Cao L, Zhang H, Yin Y, Xu X. Expression of 6 microRNAs in prostate cancer and its significance. Chin Clin Oncol. 2009;6(1):21-28.

Al-Qatati A, Akrong C, Stevic I, et al. Plasma microRNA signature is associated with risk stratification in prostate cancer patients. Int J Cancer. 2017;141(6):1231-1239.

Rabien A, Burkhardt M, Jung M, et al. Decreased RECK expression indicating proteolytic imbalance in prostate cancer is associated with higher tumor aggressiveness and risk of prostate-specific antigen relapse after radical prostatectomy. Eur Urol. 2007;51(5):1259-1266.

Bonnu C, Ramadhani A, Saputro R, et al. The potential of hsa-mir-106b-5p as liquid biomarker in prostate cancer patients in Indonesia. Asian Pac J Cancer Prev. 2021;22(3):837-842.

Sun Y, Jia X, Hou L, Liu X. Screening of differently expressed miRNA and mRNA in prostate cancer by integrated analysis of transcription data. Urology. 2016;94:313.e1-313.e6.

Huang CN, Huang SP, Pao JB, et al. Genetic polymorphisms in oestrogen receptor-binding sites affect clinical outcomes in patients with prostate cancer receiving androgen-deprivation therapy. J Intern Med. 2012;271(5):499-509.

Peskoe SB, Barber JR, Zheng Q, et al. Differential long-term stability of microRNAs and RNU6B snRNA in 12-20 year old archived formalin-fixed paraffin-embedded specimens. BMC Cancer. 2017;17(1):32.

Buitrago DH, Patnaik SK, Kadota K, Kannisto E, Jones DR, Adusumilli PS. Small RNA sequencing for profiling microRNAs in long-term preserved formalin-fixed and paraffin-embedded non-small cell lung cancer tumor specimens. PLoS One. 2015;10(3):e0121521.

McKenney JK, Wei W, Hawley S, et al. Histologic grading of prostatic adenocarcinoma can be further optimized: analysis of the relative prognostic strength of individual architectural patterns in 1275 patients from the canary retrospective cohort. Am J Surg Pathol. 2016;40(11):1439-1456.