BackgroundCirculating cell-free miRNAs have emerged as promising minimally-invasive biomarkers for early detection, prognosis and monitoring of cancer. They can exist in the bloodstream incorporated into extracellular vesicles (EVs) and ribonucleoprotein complexes. However, it is still debated if EVs contain biologically meaningful amounts of miRNAs and may provide a better source of miRNA biomarkers than whole plasma. The aim of this study was to systematically compare the diagnostic potential of prostate cancer-associated miRNAs in whole plasma and in plasma EVs.MethodsRNA was isolated from whole plasma and plasma EV samples from a well characterised cohort of 50 patient with prostate cancer (PC) and 22 patients with benign prostatic hyperplasia (BPH). Nine miRNAs known to have a diagnostic potential for PC in cell-free blood were quantified by RT-qPCR and the relative quantities were compared between patients with PC and BPH and between PC patients with Gleason score ≥ 8 and ≤6.ResultsOnly a small fraction of the total cell-free miRNA was recovered from the plasma EVs, however the EV-incorporated and whole plasma cell-free miRNA profiles were clearly different. Four of the miRNAs analysed showed a diagnostic potential in our patient cohort. MiR-375 could differentiate between PC and BPH patients when analysed in the whole plasma, while miR-200c-3p and miR-21-5p performed better when analysed in plasma EVs. EV-incorporated but not whole plasma Let-7a-5p level could distinguish PC patients with Gleason score ≥ 8 vs ≤6.ConclusionsThis study demonstrates that for some miRNA biomarkers EVs provide a more consistent source of RNA than whole plasma, while other miRNAs show better diagnostic performance when tested in the whole plasma.
Prostate cancer, the second most frequently diagnosed cancer in males worldwide, is estimated to be diagnosed in 1.1 million men per year. Introduction of PSA testing substantially improved early detection of prostate cancer, however it also led to overdiagnosis and subsequent overtreatment of patients with an indolent disease. Treatment outcome and management of prostate cancer could be improved by the development of non-invasive biomarker assays that aid in increasing the sensitivity and specificity of prostate cancer screening, help to distinguish aggressive from indolent disease and guide therapeutic decisions. Prostate cancer cells release miRNAs into the bloodstream, where they exist incorporated into ribonucleoprotein complexes or extracellular vesicles. Later, cell-free miRNAs have been found in various other biofluids. The initial RNA sequencing studies suggested that most of the circulating cell-free miRNAs in healthy individuals are derived from blood cells, while specific disease-associated miRNA signatures may appear in the circulation of patients affected with various diseases, including cancer. This raised a hope that cell-free miRNAs may serve as non-invasive biomarkers for prostate cancer. Indeed, a number of cell-free miRNAs that potentially may serve as diagnostic, prognostic or predictive biomarkers have been discovered in blood or other biofluids of prostate cancer patients and need to be validated in appropriately designed longitudinal studies and clinical trials. In this review, we systematically summarise studies investigating cell-free miRNAs in biofluids of prostate cancer patients and discuss the utility of the identified biomarkers in various clinical scenarios. Furthermore, we discuss the possible mechanisms of miRNA release into biofluids and outline the biological questions and technical challenges that have arisen from these studies.
adjacent normal tissues. The upregulated NUB1 transcripts were observed in the breast cancer. METABRIC cohort highlighted that patients with low NUB1 transcripts had a poorer survival in the ER-negative subgroup of breast cancer patients [hazard ratio (HR)=0.66, 95% confidence interval (CI)=0. 5-0.87, p=0.003] and triple negative subgroup (HR=0.67, 95% CI=0. 47-0.96, p=0.028). NUB1 knockdown inhibits in vitro cell growth in MDA-MB-231. AIPL1 protein forms multimers in cancer cells. NUB1 protein moved into the nucleus in hypoxia (0.1% O 2 48 hours). p21 and p27 proteins accumulated in NUB1-knockdown MDA-MB-231 cells. The prolonged G 0 /G 1 cell cycle arrests resulted in cell death through the neddylation-dependent CUL1-p27-p21 and CUL2-VHL axis. We also demonstrated that HIF1a protein could be neddylated upon reoxygenation. In a retrospective study of Oxford breast cancer cohort, the lower cytoplasmic expression (n=57) prognosed worse overall survival than higher cytoplasmic expression (n=57) (HR=1.779, 95% CI=1. 006-3.346, p=0.048 Introduction Sarcomas often show a limited response to current treatments. A hypothesis to explain this resistance relies on the existence of subpopulations of drug-resistant cancer stem cells (CSCs) responsible for relapses and metastasis. Therefore, there is a need for patient-close disease models amenable for testing the effect of anti-cancer therapies on CSCs. As a proof-of principle of their possible utility in future personalise medicine strategies, we have established a panel of patient-derived sarcoma primary cell lines, characterised their CSC subpopulations and tested the anti-tumour activity of the mithramycin analogue EC-8042 on these cell lines. Material and methods Fresh surgical samples of sarcomas were disaggregated and put in culture. In those cell lines adapted to grow in vitro, their proliferation ability and their potential to growth tumour xenografts were evaluated. CSCs subpopulations were characterised according to their ability to grow as tumorspheres, and the presence of cells presenting ALDH1 activity (Aldefluor © activity) or transcriptional activity due to SOX2/OCT4 in cells expressing the reporter system Sore6 (Sore6 activity). Cell survival, apoptotic induction and modulation of Sore6 activity was analysed after drug treatments. Finally, the expression/phosphorylation of signalling proteins was analysed by Western blotting. Results and discussions We have established a panel of patientderived primary cell lines able to reproduce in vivo the histopathological features of their tumours of origin. Most of these cell lines were able to grow as serially passaged tumorspheres and showed between 1% and 15% of Aldefluor © positive cells. In addition, we detected Sore6 activity in 25% of cells in a cell line expressing the Sore6 reporter. Finally, these cell lines showed a distinct sensitivity to EC8042, with IC 50 values ranging from 0.1 to 1 mM. EC-8042 was able to inhibit the expression of CSC-related factors such as SOX2, NOTCH1 and C-MYC in a dose-dependent fa...
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