Association study of microRNA genes (MIR34, MIR143, MIR145 and MIR378) and genes involved in tissue homeostasis with prostate cancer

Karcinom prostate (KP) je drugi po učestalosti maligni tumor muškaraca i predstavlja jedan od vodećih izazova savremene onkologije. Danas se intenzivno istražuju novi biološki markeri koji bi se u kombinaciji sa standardnim prognostičkim parametrima KP koristili u dijagnostici i lečenju ovih bolesnika. Kandidate za nove markere KP predstavljaju i potencijalno funkcionalne genetičke varijante sa efektom na nivoe transkripcije i/ili obradu u genima za mikroRNK kao i genetičke varijante u mestima vezivanja mikroRNK za proteine analizirane u okviru ove doktorske disertacije. Asocijacija potencijalno funkcionalnih genetičkih varijanti u regulatornim regionima gena hsa-miR-34b/c (rs4938723), hsa-miR-378 (rs1076064), hsa-miR-143/145 (rs4705342) i genima KLK3 (rs1058205), VAMP8 (rs1010) i MDM4 (rs4245739), a koje menjaju mesta vezivanja mikroRNK, analizirana je u grupi od 355 bolesnika sa KP, 358 bolesnika sa benignom hiperplazijom prostate i 370 zdravih muškaraca koji su činili kontrolnu grupu. Genotipizacija odabranih genetičkih varijanti vršena je upotrebom TaqMan eseja za genotipizaciju tačkastih genetičkih varijanti i real-time PCR-a. Nakon statističke obrade dobijenih rezultata utvrđena je asocijacija genetičke varijante rs4705354 sa povećanim rizikom za razvoj KP kod bolesnika iz populacije Srbije. Istovremeno, za genetčku varijanu rs1076064 ustanovljena je asocijacija sa rizikom za progresiju bolesti kod bolesnika iz naše populacije. Ostale analizirane genetičke varijante u okviru ove teze pokazivale su asocijaciju sa vrednostima različitih standardnih prognostičkih parametara KP. Dobijeni rezultati upućuju na to da odabrane genetičke varijante mogu biti od značaja prilikom procene rizika za progresiju tumora kod bolesnika iz naše populacije.Prostate cancer (PCa) is the most common cancer among men in Europe and one of the major medical problems in modern health practice. Novel molecular markers are urgently needed for better management and risk stratification of patients. Among the novel candidate genetic variants for the present study with the potential of becoming novel biological markers of PCa development and progression are single nucleotide variants (SNVs) with potential effect on microRNA processing/level of transcription as well as SNVs affecting the microRNA-binding mechanisms in KLK3, VAMP8 and MDM4 genes. The effect of SNVs rs4938723, rs1076064 and rs4705343 occurring in regulatory regions of miR-34b/c, miR-143/145 and miR-378, respectively, on PCa risk and progression in Serbian population was assessed on 355 patients with PCa, 358 patients with benign prostatic hyperplasia and 370 healthy volunteers. The same study group was used for evaluation of KLK3 (rs1058205), VAMP8 (rs1010) and MDM4 (rs4245739) genetic variants effect on PCa risk and progression in our population. Genotyping of selected SNVs was performed by Taqman® SNP Genotyping Assays and real-time PCR. Results were statistically evaluated and genetic variant rs4705342 was identified as PCa susceptibility variant in Serbian population, while rs1076064, rs4938723, rs1058205, rs1010 and rs4245739 showed no association with PCa risk. At the same time genetic variant rs1076064 was associated with the risk of PCa progression. Genetic variants rs4938723, rs1076064 and all three SNVs affecting microRNA binding mechanisms have shown the association with the parameters of PCa progression. The obtained results point out the potential relevance of the tested SNVs for the disease aggressiveness assessment

MiR-375 and miR-21 as Potential Biomarkers of Prostate Cancer: Comparison of Matching Samples of Plasma and Exosomes

MiR-21 and miR-375 have been reported as dysregulated in prostate cancer (PCa) in multiple previous studies. Still, variable or even opposing data for the expression of these microRNAs in PCa were found, and their potential biomarker properties remain elusive. In an attempt to clarify their significance as PCa biomarkers, as well as to compare different types of specimens as a source of relevant microRNAs, we used plasma and matching plasma-derived exosomes from patients with PCa and patients with benign prostatic hyperplasia (BPH). Plasma and exosomes were obtained from 34 patients with PCa and 34 patients with BPH, and their levels of expression of miR-21 and miR-375 were determined by RT-qPCR. We found no significant difference in the level of expression of these microRNAs in plasma and exosomes between patients with PCa and BPH. The level of exosomal miR-21 was elevated in PCa patients with high serum PSA values, as well as in patients with aggressive PCa, while for plasma samples, the results remained insignificant. For miR-375, we did not find an association with the values of standard prognostic parameters of PCa, nor with cancer aggressiveness. Therefore, our results support the potential prognostic role of exosomal miR-21 expression levels in PCa

Association study of microRNA genes (MIR34, MIR143, MIR145 and MIR378) and genes involved in tissue homeostasis with prostate cancer

Karcinom prostate (KP) je drugi po učestalosti maligni tumor muškaraca i predstavlja jedan od vodećih izazova savremene onkologije. Danas se intenzivno istražuju novi biološki markeri koji bi se u kombinaciji sa standardnim prognostičkim parametrima KP koristili u dijagnostici i lečenju ovih bolesnika. Kandidate za nove markere KP predstavljaju i potencijalno funkcionalne genetičke varijante sa efektom na nivoe transkripcije i/ili obradu u genima za mikroRNK kao i genetičke varijante u mestima vezivanja mikroRNK za proteine analizirane u okviru ove doktorske disertacije. Asocijacija potencijalno funkcionalnih genetičkih varijanti u regulatornim regionima gena hsa-miR-34b/c (rs4938723), hsa-miR-378 (rs1076064), hsa-miR-143/145 (rs4705342) i genima KLK3 (rs1058205), VAMP8 (rs1010) i MDM4 (rs4245739), a koje menjaju mesta vezivanja mikroRNK, analizirana je u grupi od 355 bolesnika sa KP, 358 bolesnika sa benignom hiperplazijom prostate i 370 zdravih muškaraca koji su činili kontrolnu grupu. Genotipizacija odabranih genetičkih varijanti vršena je upotrebom TaqMan eseja za genotipizaciju tačkastih genetičkih varijanti i real-time PCR-a. Nakon statističke obrade dobijenih rezultata utvrđena je asocijacija genetičke varijante rs4705354 sa povećanim rizikom za razvoj KP kod bolesnika iz populacije Srbije. Istovremeno, za genetčku varijanu rs1076064 ustanovljena je asocijacija sa rizikom za progresiju bolesti kod bolesnika iz naše populacije. Ostale analizirane genetičke varijante u okviru ove teze pokazivale su asocijaciju sa vrednostima različitih standardnih prognostičkih parametara KP. Dobijeni rezultati upućuju na to da odabrane genetičke varijante mogu biti od značaja prilikom procene rizika za progresiju tumora kod bolesnika iz naše populacije.Prostate cancer (PCa) is the most common cancer among men in Europe and one of the major medical problems in modern health practice. Novel molecular markers are urgently needed for better management and risk stratification of patients. Among the novel candidate genetic variants for the present study with the potential of becoming novel biological markers of PCa development and progression are single nucleotide variants (SNVs) with potential effect on microRNA processing/level of transcription as well as SNVs affecting the microRNA-binding mechanisms in KLK3, VAMP8 and MDM4 genes. The effect of SNVs rs4938723, rs1076064 and rs4705343 occurring in regulatory regions of miR-34b/c, miR-143/145 and miR-378, respectively, on PCa risk and progression in Serbian population was assessed on 355 patients with PCa, 358 patients with benign prostatic hyperplasia and 370 healthy volunteers. The same study group was used for evaluation of KLK3 (rs1058205), VAMP8 (rs1010) and MDM4 (rs4245739) genetic variants effect on PCa risk and progression in our population. Genotyping of selected SNVs was performed by Taqman® SNP Genotyping Assays and real-time PCR. Results were statistically evaluated and genetic variant rs4705342 was identified as PCa susceptibility variant in Serbian population, while rs1076064, rs4938723, rs1058205, rs1010 and rs4245739 showed no association with PCa risk. At the same time genetic variant rs1076064 was associated with the risk of PCa progression. Genetic variants rs4938723, rs1076064 and all three SNVs affecting microRNA binding mechanisms have shown the association with the parameters of PCa progression. The obtained results point out the potential relevance of the tested SNVs for the disease aggressiveness assessment

Analysis of association of potentially functional genetic variants within genes encoding miR-34b/c, miR-378 and miR-143/145 with prostate cancer in Serbian population

MiRNA-associated genetic variants occurring in regulatory regions can affect the efficiency of transcription and potentially modify pri-miRNA or pre-miRNA processing. Since miRNA-based mechanisms are shown to be involved in the pathogenesis of prostate cancer (PCa), the aim of the present study was to evaluate the effect of rs4938723, rs1076064 and rs4705343 occurring in regulatory regions of miR-34b/c, miR-143/145 and miR-378, respectively, on PCa risk and progression in Serbian popul ation. We examined a total of 1060 subjects, of which 350 were patients with PCa, 354 were patients with benign prostatic hyperplasia (BPH), while 356 healthy volunteers were included in the control group. Genotyping of rs4938723, rs1076064 and rs4705343 was performed by using Taqman® SNP Genotyping Assays. Allele C of rs4705342 was found to increase the risk of PCa (P=0.031 for codominant model, P=0.0088 for recessive model). Rs1076064 minor allele G was found to associate with serum PSA score, as well as with PCa T category and disease aggressiveness. For rs4938723 minor allele C was shown to be associated with the lower PCa T category (Pdom=0.0046; OR=0.36, 95 % CI 0.17-0.76) in T2 vs. T1 comparison. Rs4705342 was identified as PCa susceptibility variant in Serbian population, while for rs1076064 and rs4938723 association with PCa progression parameters was found