Urinary extracellular miRNAs as potential biomarkers for castration-resistant prostate cancer
https://doi.org/10.21294/1814-4861-2025-24-4-82-92
Abstract
Background. Castration-resistant prostate cancer (CRPC) is a highly aggressive and challenging-to-treat cancer. the search for markers to predict early CRPC for timely treatment adjustments and further study of these markers as potential targets for new CRPC therapies is a crucial task in modern molecular biology and medicine. extracellular miRnas show promise as diagnostic and prognostic markers for prostate cancer (PC) and particular for CRPC.
Aim of the study: a comparative analysis of the expression of 14 miRnas in the urine supernatant of patients with hormone-sensitive prostate cancer (HsPC), CRPC, and donors (D).
Material and Methods. the analysis was conducted using the real-time qPCR. a pairwise normalization method was used to search for diagnostic miRna expression signatures.
Results. twenty-nine differentially expressed pairs of miRnas were identified. In this case, miRna-375 was included in the largest number (n=7) of diagnostically significant pairs. three miRna pairs (miRna-144/222; 205/375; 222/125) showed the highest sensitivity and specificity in diagnosing CRPC when using both HsPC patients alone and the combined group of donors and HsPC patients as the control group.
Conclusion. the results obtained indicate that the assessment of the relative expression of urinary extracellular miRnas has a significant potential for diagnosing highly aggressive castration-resistant prostate cancer.
Keywords
prostate cancer,
castration-resistant prostate cancer,
extracellular microRnas,
diagnosis,
liquid biopsy
Supporting agencies: The study was carried out within the framework of basic budget funding projects of the Russian Ministry of Education and Science (No. 125012900932-4).
About the Authors
M. M. Saitkulova
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Milena M. Saitkulova, Laboratory Assistant-Researcher
Author ID (Scopus): 55204686500
8, Lavrentiev ave., Novosibirsk, 630090
O. E. Bryzgunova
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Olga E. Bryzgunova, PhD, Senior Researcher
Author ID (Scopus): 6507738308
8, Lavrentiev ave., Novosibirsk, 630090
I. A. Ostaltsev
National Medical Research Center named after ak. E.N. Meshalkin, Ministry of Health of Russia
Russian Federation
Russian Federation
Ilya A. Ostaltsev, MD, Oncologist
Author ID (Scopus): 59187089900
15, Rechkunovskaya st., Novosibirsk, 630055
S. V. Pak
National Medical Research Center named after ak. E.N. Meshalkin, Ministry of Health of Russia
Russian Federation
Russian Federation
Svetlana V. Pak, Head of the Blood Transfusion Department
Author ID (Scopus): 57208228505
15, Rechkunovskaya st., Novosibirsk, 630055
P. P. Laktionov
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Pavel P. Laktionov, MD, PhD, Head of Laboratory
Author ID (Scopus): 7003559490
8, Lavrentiev ave., Novosibirsk, 630090
M. Yu. Konoshenko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
Russian Federation
Russian Federation
Maria Yu. Konoshenko, MD, PhD, Senior Researcher
Author ID (Scopus): 55204686500
8, Lavrentiev ave., Novosibirsk, 630090
References
1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–49. doi: 10.3322/caac.21660.
2. American Cancer Society. Cancer Facts & Figures 2023. Atlanta: American Cancer Society; 2023. [Internet]. [cited 02.08.2024]. URL: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf.
3. Malignant tumors in Russia in 2021 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow, 2022. 252 p. (in Russian). ISBN: 978-5-85502-280-3.
4. Meng M.V., Grossfeld G.D., Sadetsky N., Mehta S.S., Lubeck D.P., Carroll P.R. Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology. 2002; 60(3): 7–11. doi: 10.1016/s0090-4295(02)01560-1.
5. Rusakov I.G., Gritskevich A.A., Baitman T.P., Mishugin S.V. The castration level of testosterone and hormonal resistance of prostate cancer in androgen deprivation therapy. Medical Council. 2020; 20: 100–108. (in Russian). doi: 10.21518/2079-701X-2020-20-100-108. EDN: WVAHFQ.
6. Khoshkar Y., Westerberg M., Adolfsson J., Bill-Axelson A., Olsson H., Eklund M., Akre O., Garmo H., Aly M. Mortality in men with castrationresistant prostate cancer-A long-term follow-up of a population-based real-world cohort. BJUI Compass. 2021; 3(2): 173–83. doi: 10.1002/bco2.116.
7. Cornford P., van den Bergh R.C.N., Briers E., van den Broeck T., Brunckhorst O., Darraugh J., Eberli D., De Meerleer G., De Santis M., Farolfi A., Gandaglia G., Gillessen S., Grivas N., Henry A.M., Lardas M., van Leenders G.J.L.H., Liew M., Linares Espinos E., Oldenburg J., van Oort I.M., Oprea-Lager D.E., Ploussard G., Roberts M.J., Rouvière O., Schoots I.G., Schouten N., Smith E.J., Stranne J., Wiegel T., Willemse P.M., Tilki D. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2024; 86(2): 148–63. doi: 10.1016/j.eururo.2024.03.027.
8. Chang H.L., Yang L.F., Zhu Y., Yao X.D., Zhang S.L., Dai B., Zhu Y.P., Shen Y.J., Shi G.H., Ye D.W. Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate. 2011; 71(3): 326–31. doi: 10.1002/pros.21246.
9. Konoshenko M.Y., Bryzgunova O.E., Laktionov P.P. miRNAs and androgen deprivation therapy for prostate cancer. Biochim Biophys Acta Rev Cancer. 2021 Dec; 1876(2): 188625. doi: 10.1016/j.bbcan.2021.188625
10. Konoshenko M.Y., Lekchnov E.A., Bryzgunova O.E., Zaporozhchenko I.A., Yarmoschuk S.V., Pashkovskaya O.A., Pak S.V., Laktionov P.P. The Panel of 12 Cell-Free MicroRNAs as Potential Biomarkers in Prostate Neoplasms. Diagnostics (Basel). 2020; 10(1): 38. doi: 10.3390/diagnostics10010038.
11. Sun X.B., Chen Y.W., Yao Q.S., Chen X.H., He M., Chen C.B., Yang Y., Gong X.X., Huang L. MicroRNA-144 Suppresses Prostate Cancer Growth and Metastasis by Targeting EZH2. Technol Cancer Res Treat. 2021; 20: 1533033821989817. doi: 10.1177/1533033821989817.
12. Fredsøe J., Rasmussen A.K.I., Thomsen A.R., Mouritzen P., Høyer S., Borre M., Ørntoft T.F., Sørensen K.D. Diagnostic and Prognostic MicroRNA Biomarkers for Prostate Cancer in Cell-free Urine. Eur Urol Focus. 2018; 4(6): 825–33. doi: 10.1016/j.euf.2017.02.018.
13. Aghdam A.M., Amiri A., Salarinia R., Masoudifar A., Ghasemi F., Mirzaei H. MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer. Crit Rev Eukaryot Gene Expr. 2019; 29(2): 127–39. doi: 10.1615/CritRevEukaryotGeneExpr.2019025273.
14. Boeri M., Verri C., Conte D., Roz L., Modena P., Facchinetti F., Calabrò E., Croce C.M., Pastorino U., Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci USA. 2011; 108: 3713–18. doi: 10.1073/pnas.1100048108.
15. Gan J., Liu S., Zhang Y., He L., Bai L., Liao R., Zhao J., Guo M., Jiang W., Li J., Li Q., Mu G., Wu Y., Wang X., Zhang X., Zhou D., Lv H., Wang Z., Zhang Y., Qian C., Feng M., Chen H., Meng Q., Huang X. MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis. Exp Mol Med. 2022; 54(8): 1290–305. doi: 10.1038/s12276-022-00837-6.
16. Lekchnov E.A., Amelina E.V., Bryzgunova O.E., Zaporozhchenko I.A., Konoshenko M.Y., Yarmoschuk S.V., Murashov I.S., Pashkovskaya O.A., Gorizkii A.M., Zheravin A.A., Laktionov P.P. Searching for the Novel Specific Predictors of Prostate Cancer in Urine: The Analysis of 84 miRNA Expression. Int J Mol Sci. 2018; 19(12): 4088. doi: 10.3390/ijms19124088.
17. Rishik S., Hirsch P., Grandke F., Fehlmann T., Keller A. miRNATissueAtlas 2025: an update to the uniformly processed and annotated human and mouse non-coding RNA tissue atlas. Nucleic Acids Res. 2025; 53(D1): 129–37. doi: 10.1093/nar/gkae1036.
18. Hasanoğlu S., Göncü B., Yücesan E., Atasoy S., Kayalı Y., Özten Kandaş N. Investigating differential miRNA expression profiling using serum and urine specimens for detecting potential biomarkers for early prostate cancer diagnosis. Turk J Med Sci. 2021; 51(4): 1764–74. doi: 10.3906/sag-2010-183.
19. Stuopelyte K., Daniunaite K., Bakavicius A., Lazutka J.R., Jankevicius F., Jarmalaite S. The utility of urine-circulating miRNAs for detection of prostate cancer. Br J Cancer. 2016; 115(6): 707–15. doi: 10.1038/bjc.2016.233.
20. Ghorbanmehr N., Gharbi S., Korsching E., Tavallaei M., Einollahi B., Mowla S.J. miR-21-5p, miR-141-3p, and miR-205-5p levels in urine-promising biomarkers for the identification of prostate and bladder cancer. Prostate. 2019; 79(1): 88–95. doi: 10.1002/pros.23714.
21. Chauhan N., Manojkumar A., Jaggi M., Chauhan S.C., Yallapu M.M. microRNA-205 in prostate cancer: Overview to clinical translation. Biochim Biophys Acta Rev Cancer. 2022; 1877(6): 188809. doi: 10.1016/j.bbcan.2022.188809.
22. Wang W., Kong P., Feng K., Liu C., Gong X., Sun T., Duan X., Sang Y., Jiang Y., Li X., Zhang L., Tao Z., Liu W. Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling. Cancer Sci. 2023; 114(11): 4252–69. doi: 10.1111/cas.15948.
23. Song Q., An Q., Niu B., Lu X., Zhang N., Cao X. Role of miR- 221/222 in Tumor Development and the Underlying Mechanism. J Oncol. 2019; 2019: 7252013. doi: 10.1155/2019/7252013.
24. Yu J., Lu Y., Cui D., Li E., Zhu Y., Zhao Y., Zhao F., Xia S. miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol Rep. 2014; 31(2): 910–18. doi: 10.3892/or.2013.2897.
25. Peng B., Theng P.Y., Le M.T.N. Essential functions of miR-125b in cancer. Cell Prolif. 2021; 54(2): e12913. doi: 10.1111/cpr.12913.
26. Budd W.T., Seashols-Williams S.J., Clark G.C., Weaver D., Calvert V., Petricoin E., Dragoescu E.A., O’Hanlon K., Zehner Z.E. Dual Action of miR-125b As a Tumor Suppressor and OncomiR-22 Promotes Prostate Cancer Tumorigenesis. PLoS One. 2015; 10(11): e0142373. doi: 10.1371/journal.pone.0142373.
27. Nosov A.K., Vorobyov N.A. Hormone-resistant prostate cancer. Practical Oncology. 2008; 9(2): 104–16. (in Russian). EDN: QCQJMT.
Supplementary files
|
|
1. Fig. 1. Examples of microRNA pairs whose relative expression significantly differs in the cell-free urine fraction of the researched groups. The values of ΔCt are given. Pairwise comparisons according to the criteria of Tukey and Dunn: * – p<0.05, ** – p<0.01, *** – p<0.001, **** – p<0.0001. Notes: CRPCa – castration resistant prostate cancer; HSPCa – hormone sensitive prostate cancer; D – donors; created by the authors | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(39KB)
|
Indexing metadata ▾ | |
|
|
2. Fig. 2. ROC analysis of the relative expression of microRNA pairs of the cell-free fraction of urine of patients with CRPC characterized by the highest AUC. A – patients with HSPC as a control group; B – combined group D and patients with HSPC as a control group. Notes: CRPCa – castration resistant prostate cancer; HSPCa – hormone sensitive prostate cancer; D – donors; AUC – area under curve; created by the authors | |
| Subject | ||
| Type | Исследовательские инструменты | |
View
(100KB)
|
Indexing metadata ▾ | |
Review
For citations:
Saitkulova M.M., Bryzgunova O.E., Ostaltsev I.A., Pak S.V., Laktionov P.P., Konoshenko M.Yu. Urinary extracellular miRNAs as potential biomarkers for castration-resistant prostate cancer. Siberian journal of oncology. 2025;24(4):82-92. (In Russ.) https://doi.org/10.21294/1814-4861-2025-24-4-82-92
Views:
20
Email this article 
