Prostat Kanserinde Tanısal Biyobelirteçler Olarak Sirküle miRNA’ların Rolü
Özet
Prostat kanseri (PKa), erkeklerde kansere bağlı ölümlerin ikinci yaygın nedeni olup, mevcut tarama aracı olan serum PSA ölçümlerinin spesifik olmaması nedeniyle aşırı teşhis ve tedavi gibi sorunlara yol açmaktadır. Bu durum, teşhis, prognoz ve tedavi takibi için yeni ve güvenilir biyobelirteç arayışını tetiklemiş ve yaklaşık 22 nükleotitten oluşan küçük, kodlamayan RNA molekülleri olan mikroRNA'ları (miRNA) ön plana çıkarmıştır. Endojen miRNA'lar, hedef mRNA'ları baskılayarak hücre döngüsü, apoptoz, metastaz ve epitel-mezenkimal geçiş (EMT) gibi kritik hücresel süreçleri modüle eder. Vücut sıvılarında lipid mikroveziküller içinde veya proteinlerle kompleks halinde bulunmaları, onları ribonükleazlara ve zorlu fizikokimyasal koşullara karşı son derece dayanıklı hale getirir. Kan, idrar ve meni gibi biyolojik sıvılardan non-invaziv yollarla izole edilebilen sirküle miRNA'lar; qRT-PCR, mikroarray ve yeni nesil dizileme (NGS) gibi standart tekniklerle kolayca saptanabilir. Klinik çalışmalarda miR-141, miR-21, miR-221 ve miR-320 gibi spesifik sirküle miRNA panellerinin, PKa'yı iyi huylu prostat hiperplazisinden (BPH) ve sağlıklı kontrollerden yüksek doğrulukla ayırt edebildiği, ayrıca agresif ve metastatik formları öngörebildiği gösterilmiştir. Ancak, salınım mekanizmalarının tam anlaşılamaması, standardizasyon ve kararlı bir endojen kontrol (normalizasyon) eksikliği ile metodolojik farklılıklar rutin klinik kullanımı kısıtlamaktadır. Gelecekte bu kısıtlılıkların aşılmasıyla sirküle miRNA'ların PKa yönetiminde umut verici yeni nesil biyobelirteçler olması beklenmektedir.
Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men, and because current serum PSA screening lacks specificity, it leads to issues such as overdiagnosis and overtreatment. This situation has triggered the search for new, reliable biomarkers for diagnosis, prognosis, and treatment monitoring, highlighting microRNAs (miRNAs), which are small, non-coding RNA molecules consisting of approximately 22 nucleotides. Endogenous miRNAs modulate critical cellular processes like the cell cycle, apoptosis, metastasis, and epithelial-mesenchymal transition (EMT) by suppressing target mRNAs. Their presence within lipid microvesicles or complexed with proteins in body fluids makes them highly resistant to ribonucleases and harsh physicochemical conditions. Circulating miRNAs, which can be isolated non-invasively from biological fluids such as blood, urine, and semen, are easily detectable via standard techniques like qRT-PCR, microarray, and next-generation sequencing (NGS). Clinical studies have shown that specific circulating miRNA panels, including miR-141, miR-21, miR-221, and miR-320, can distinguish PCa from benign prostatic hyperplasia (BPH) and healthy controls with high accuracy, as well as predict aggressive and metastatic forms. However, gaps in understanding release mechanisms, the lack of standardized endogenous controls for normalization, and methodological variations currently limit their routine clinical use. Overcoming these limitations in the near future will undoubtedly establish circulating miRNAs as promising next-generation biomarkers in PCa management.
Referanslar
Velonas VM, Woo HH, dos Remedios CG, et al. Current status of biomarkers for prostate cancer. International journal of molecular sciences. 2013;14(6):11034-11060. doi:10.3390/ijms140611034
Sita-Lumsden A, Dart DA, Waxman J, et al. Circulating microRNAs as potential new biomarkers for prostate cancer. British journal of cancer. 2013;108(10):1925-1930. doi:10.1038/bjc.2013.192
Madu CO, Lu Y. Novel diagnostic biomarkers for prostate cancer. Journal of Cancer. 2010;1:150-177. doi:10.7150/jca.1.150
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer Journal of Clinicians. 2018;68(6):394-424. doi:10.3322/caac.21492
Vanacore D, Boccellino M, Rossetti S, et al. Micrornas in prostate cancer: an overview. Oncotarget. 2017;8(30):50240-50251. doi:10.18632/oncotarget.16933
Sapre N, Selth LA. Circulating MicroRNAs as Biomarkers of Prostate Cancer: The State of Play. Prostate Cancer. 2013;2013:539680. doi:10.1155/2013/539680
Nakagawa M. Nihon rinsho. Japanese journal of clinical medicine. 2014;72(12):2224-2228.
Boccellino M, Alaia C, Misso G, et al. Gene interference strategies as a new tool for the treatment of prostate cancer. Endocrine. 2015;49(3):588-605. doi:10.1007/s12020-015-0629-3
Sartori DA, Chan DW. Biomarkers in prostate cancer: what's new?. Current opinion in oncology. 2014;26(3):259-264. doi:10.1097/CCO.0000000000000065
Ibrahim NH, Abdellateif MS, Kassem SH, et al. Diagnostic significance of miR-21, miR-141, miR-18a and miR-221 as novel biomarkers in prostate cancer among Egyptian patients. Andrologia. 2019;51(10):e13384. doi:10.1111/and.13384
Haldrup C, Kosaka N, Ochiya T, et al. Profiling of circulating microRNAs for prostate cancer biomarker discovery. Drug delivery and translational research. 2014;4(1):19-30. doi:10.1007/s13346-013-0169-4
Matin F, Jeet V, Moya L, et al. A Plasma Biomarker Panel of Four MicroRNAs for the Diagnosis of Prostate Cancer. Scientific reports. 2018;8(1):6653. doi:10.1038/s41598-018-24424-w
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-297. doi:10.1016/s0092-8674(04)00045-5
Das DK, Persaud L, Sauane M. MicroRNA-4719 and microRNA-6756-5p Correlate with Castration-Resistant Prostate Cancer Progression through Interleukin-24 Regulation. Noncoding RNA. 2019;5(1):10. doi:10.3390/ncrna5010010
Wahid F, Shehzad A, Khan T, et al. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochimica et biophysica acta. 2010;1803(11):1231-1243. doi:10.1016/j.bbamcr.2010.06.013
Madu CO, Lu Y. Novel diagnostic biomarkers for prostate cancer. J Cancer. 2010;1:150-177. doi:10.7150/jca.1.150
Biomarkers Definitions Working Group.. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics. 2001;69(3):89-95. doi:10.1067/mcp.2001.113989
Lan H, Lu H, Wang X, et al. MicroRNAs as potential biomarkers in cancer: opportunities and challenges. BioMed research international. 2015;2015:125094. doi:10.1155/2015/125094
Tricoli JV, Schoenfeldt M, Conley BA. Detection of prostate cancer and predicting progression: current and future diagnostic markers. Clinical cancer research. 2004;10(12 Pt 1):3943-3953. doi:10.1158/1078-0432.CCR-03-0200
Hartwell L, Mankoff D, Paulovich A, et al. Cancer biomarkers: a systems approach. Nature biotechnology. 2006;24(8):905-908. doi:10.1038/nbt0806-905
Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(30):10513-10518. doi:10.1073/pnas.0804549105
Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834-838. doi:10.1038/nature03702
Fabris L, Ceder Y, Chinnaiyan AM, et al. The potential of microRNAs as prostate cancer biomarkers. European urology. 2016;70(2):312-322. doi:10.1016/j.eururo.2015.12.054
Schwarzenbach H, da Silva AM, Calin G, et al. Data normalization strategies for microRNA quantification. Clinical chemistry. 2015;61(11):1333-1342. doi:10.1373/clinchem.2015.239459
Cortez MA, Bueso-Ramos C, Ferdin J, et al. MicroRNAs in body fluids--the mix of hormones and biomarkers. Nature reviews Clinical oncology. 2011;8(8):467-477. doi:10.1038/nrclinonc.2011.76
Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell research. 2008;18(10):997-1006. doi:10.1038/cr.2008.282
Mall C, Rocke DM, Durbin-Johnson B, et al. Stability of miRNA in human urine supports its biomarker potential. Biomarkers in medicine. 2013;7(4):623-631. doi:10.2217/bmm.13.44
Dong JT, Isaacs WB, Isaacs JT. Molecular advances in prostate cancer. Current opinion in oncology. 1997;9(1):101-107. doi:10.1097/00001622-199701000-00016
Filella X, Foj L. miRNAs as novel biomarkers in the management of prostate cancer. Clinical chemistry and laboratory medicine. 2017;55(5):715-736. doi:10.1515/cclm-2015-1073
Lewis H, Lance R, Troyer D, et al. miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration. Cell Cycle. 2014;13(2):227-239. doi:10.4161/cc.26984
Coolen MW, Stirzaker C, Song JZ, et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nature cell biology. 2010;12(3):235-246. doi:10.1038/ncb2023
Zhou Y, Bolton EC, Jones JO. Androgens and androgen receptor signaling in prostate tumorigenesis. Journal of molecular endocrinology. 2015;54(1):R15-R29. doi:10.1530/JME-14-0203
ChunJiao S, Huan C, ChaoYang X, et al. Uncovering the roles of miRNAs and their relationship with androgen receptor in prostate cancer. IUBMB Life. 2014;66(6):379-386. doi:10.1002/iub.1281
Jalava SE, Urbanucci A, Latonen L, et al. Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer. Oncogene. 2012;31(41):4460-4471. doi:10.1038/onc.2011.624
Dong Q, Meng P, Wang T, et al. MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS One. 2010;5(4):e10147. doi:10.1371/journal.pone.0010147
Szczyrba J, Löprich E, Wach S, et al. The microRNA profile of prostate carcinoma obtained by deep sequencing. Molecular cancer research. 2010;8(4):529-538. doi:10.1158/1541-7786.MCR-09-0443
Schaefer A, Jung M, Mollenkopf HJ, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. International journal of cancer. 2010;126(5):1166-1176. doi:10.1002/ijc.24827
Bonci D, Coppola V, Musumeci M, et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nature medicine. 2008;14(11):1271-1277. doi:10.1038/nm.1880
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. Journal of clinical investigation. 2009;119(6):1420-1428. doi:10.1172/JCI39104
Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature cell biology. 2008;10(5):593-601. doi:10.1038/ncb1722
Vandewalle C, Comijn J, De Craene B, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 2005;33(20):6566-6578. doi:10.1093/nar/gki965
Lawrie CH, Gal S, Dunlop HM, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. British journal of haematology. 2008;141(5):672-675. doi:10.1111/j.1365-2141.2008.07077.x
Lieb V, Weigelt K, Scheinost L, et al. Serum levels of miR-320 family members are associated with clinical parameters and diagnosis in prostate cancer patients. Oncotarget. 2017;9(12):10402-10416. doi:10.18632/oncotarget.23781
Srivastava A, Goldberger H, Dimtchev A, et al. Circulatory miR-628-5p is downregulated in prostate cancer patients. Tumour Biology. 2014;35(5):4867-4873. doi:10.1007/s13277-014-1638-1
Moltzahn F, Olshen AB, Baehner L, et al. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Research. 2011;71(2):550-560. doi:10.1158/0008-5472.CAN-10-1229
Brase JC, Johannes M, Schlomm T, et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. International journal of cancer. 2011;128(3):608-616. doi:10.1002/ijc.25376
Yaman Agaoglu F, Kovancilar M, Dizdar Y, et al. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biology. 2011;32(3):583-588. doi:10.1007/s13277-011-0154-9
Kotb S, Mosharafa A, Essawi M, Hassan H, Meshref A, Morsy A. Circulating miRNAs 21 and 221 as biomarkers for early diagnosis of prostate cancer. Tumour Biol. 2014;35(12):12613-12617. doi:10.1007/s13277-014-2584-7
Shen J, Hruby GW, McKiernan JM, et al. Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer. Prostate. 2012;72(13):1469-1477. doi:10.1002/pros.22499
Watahiki A, Macfarlane RJ, Gleave ME, et al. Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer. International journal of molecular sciences. 2013;14(4):7757-7770. doi:10.3390/ijms14047757
Cozar JM, Robles-Fernandez I, Rodriguez-Martinez A, et al. The role of miRNAs as biomarkers in prostate cancer. Mutation research reviews in mutation research. 2019;781:165-174. doi:10.1016/j.mrrev.2019.05.005
Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clinical chemistry. 2015;61(1):56-63. doi:10.1373/clinchem.2014.221341
Kappel A, Keller A. miRNA assays in the clinical laboratory: workflow, detection technologies and automation aspects. Clinical chemistry and laboratory medicine. 2017;55(5):636-647. doi:10.1515/cclm-2016-0467
Marzi MJ, Montani F, Carletti RM, et al. Optimization and Standardization of Circulating MicroRNA Detection for Clinical Application: The miR-Test Case. Clinical chemistry. 2016;62(5):743-754. doi:10.1373/clinchem.2015.251942
Valadi H, Ekström K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature cell biology. 2007;9(6):654-659. doi:10.1038/ncb1596
Peltier HJ, Latham GJ. Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA. 2008;14(5):844-852. doi:10.1261/rna.939908
