MicroRNA-4719 and microRNA-6756-5p Correlate with Castration-Resistant Prostate Cancer Progression through Interleukin-24 Regulation (original) (raw)
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Oncotarget, 2014
Our recent study of microRNA (miRNA) expression signatures in prostate cancer (PCa) has revealed that all members of the miR-23b/27b/24-1 cluster are significantly downregulated in PCa tissues. The aim of this study was to investigate the effectiveness of these clustered miRNAs as a disease progression marker and to determine the functional significance of these clustered miRNAs in PCa. Expression of the miR-23b/27b/24-1 cluster was significantly reduced in PCa tissues. Kaplan-Meier survival curves showed that low expression of miR-27b predicted a short duration of progression to castration-resistant PCa. Gain-of-function studies using mature miR-23b, miR-27b,and miR-24-1 significantly inhibited cell proliferation, migration and invasion in PCa cells (PC3 and DU145). To identify the molecular targets of these miRNAs, we carried out gene expression and in silico database analyses. GOLM1 was directly regulated by miR-27b in PCa cells. Elucidation of the molecular targets and pathways ...
European urology, 2015
Systematic approaches to functionally identify key players in microRNA (miRNA)-target networks regulating prostate cancer (PCa) proliferation are still missing. To comprehensively map miRNA regulation of genes relevant for PCa proliferation through phenotypic screening and tumor expression data. Gain-of-function screening with 1129 miRNA molecules was performed in five PCa cell lines, measuring proliferation, viability, and apoptosis. These results were integrated with changes in miRNA expression from two cohorts of human PCa (188 tumors in total). For resulting miRNAs, the predicted targets were collected and analyzed for patterns with gene set enrichment analysis, and for their association with biochemical recurrence free survival. Rank product statistical analysis was used to evaluate miRNA effects in phenotypic screening and for expression differences in the prostate tumor cohorts. Expression data were analyzed using the significance analysis of microarrays (SAM) method and the ...
Downregulation and Prognostic Performance of MicroRNA 224 Expression in Prostate Cancer
Clinical Chemistry, 2013
INTRODUCTION The extensive use of prostate-specific antigen as a general prostate cancer biomarker has introduced the hazards of overdiagnosis and overtreatment. Recent studies have revealed the immense biomarker capacity of microRNAs (miRNAs) in prostate cancer. The aim of this study was to analyze the expression pattern of miR-224, a cancer-related miRNA, in prostate tumors and investigate its clinical utility. METHODS Total RNA was isolated from 139 prostate tissue samples. After the polyadenylation of total RNA by poly(A) polymerase, cDNA was synthesized with a suitable poly(T) adapter. miR-224 expression was assessed by quantitative real-time PCR and analyzed with the comparative quantification cycle method, Cq(2−ΔΔCq). We performed comprehensive biostatistical analyses to explore the clinical value of miR-224 in prostate cancer. RESULTS miR-224 expression was significantly downregulated in malignant samples compared with benign samples (P < 0.001). Higher miR-224 expression...
2021
Prostate cancer (PCa) is a leading cause of cancer-related death. Upon androgen-deprivation therapy, the disease may progress further to castration-resistant PCa (CRPC) with a poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs, which play crucial roles in gene regulation. The aim of our study is to find CRPC-associated miRNAs and to evaluate their functional role. In this study, 23 benign prostatic hyperplasia (BPH), 76 primary PCa, and 35 CRPC specimens were included. Total RNA extracted from tissue sections was used for miRNA profiling on the Affymetrix GSC 3000 platform. Subsequently, stem-loop RT-qPCR analysis was performed to validate the expression levels of selected miRNAs. PCa cell lines were transfected with miRNA mimics or inhibitors to evaluate the effects on cell proliferation, cell migration and cell invasion. In our profiling study, several miRNAs were found to be deregulated in CRPC compared to primary PCa tissue, of which miR-205 (− 4.5-fold; p = 0.0009), m...
Identification of microRNA signature and potential pathway targets in prostate cancer
Experimental biology and medicine (Maywood, N.J.), 2016
Prostate cancer (PC) is the most common and the second leading cause of cancer-related death among American men. Early diagnosis is a prerequisite to improving therapeutic benefits. However, the current clinical biomarkers for PC do not reliably decipher indolent PC from other urogenital disorders. Thus, effective clinical intervention necessitates development of new biomarkers for early detection of PC. The present study aimed to identify the miRNA signature in organ-confined (Gleason Score 6) prostate tumors. MicroRNA (miRNA/miR) array analysis identified 118 upregulated and 73 downregulated miRNAs in microdissected tumors in comparison to matched neighboring normal prostate epithelium. The miRs-Plus-A1083, -92b-5p, -18a-3p, -19a-3p, -639, -3622b-3p, -3189-3p, -155-3p, -410, -1179, 548b-5p, and -4469 are predominantly expressed (7-11-fold), whereas miRs-595, 4490, -3120-5p, -1299, -21-5p, -3677-3, -let-7b-5p, -5189, 3-121-5p, -4518, -200a-5p, -3682-5p, -3689d, -3149 represent the ...
MicroRNA Dysregulation in Prostate Cancer
Pharmacogenomics and Personalized Medicine, 2022
Prostate cancer biology is complex, and needs to be deciphered. The latest evidence reveals the significant role of noncoding RNAs, particularly microRNAs (miRNAs), as key regulatory factors in cancer. Therefore, the identification of altered miRNA patterns involved in prostate cancer will allow them to be used for development of novel diagnostic and prognostic biomarkers. Patients and Methods: We performed a miRNAs transcriptomic analysis, using microarray (10 matched pairs tumor tissue versus normal adjacent tissue, selected based on inclusion criteria), followed by overlapping with TCGA data. A total of 292 miRNAs were differentially expressed, with 125 upregulated and 167 downregulated in TCGA patients' cohort with PRAD (prostate adenocarcinoma), respectively for the microarray experiments; 16 upregulated and 44 downregulated miRNAs were found in our cohort. To confirm our results obtained for tumor tissue, we performed validation with qRT-PCR at the tissue and plasma level of two selected transcripts, and finally, we focused on the identification of altered miRNAs involved in key biological processes. Results: A common signature identified a panel of 12 upregulated and 1 downregulated miRNA, targeting and interconnected in a network with the TP53, AGO2, BIRC5 gene and EGFR as a core element. Among this signature, the overexpressed transcripts (miR-20b-5p, miR-96-5p, miR-183-5p) and the downregulated miR-542-5p were validated by qRT-PCR in an additional patients' cohort of 34 matched tumor and normal adjacent paired samples. Further, we performed the validation of the expression level for miR-20b-5p, miR-96-5p, miR-183-5p plasma, on the same patients' cohort versus a healthy control group, confirming the overexpression of these transcripts in the PRAD group, demonstrating the liquid biopsy as a potential investigational tool in prostate cancer. Conclusion: In this pilot study, we provide evidence on miRNA dysregulation and its association with key functional components of the PRAD landscape, where an important role is acted by miR-20b-5p, miR-542-5p, or the oncogenic cluster miR-183-96-182.
Journal of Human Genetics, 2012
microRNAs (miRNAs) have key roles in human tumorigenesis, tumor progression and metastasis. miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. This study seeks to identify novel miRNA-regulated molecular pathways in prostate cancer (PCa). The miRNA expression signature in clinical specimens of PCa showed that 56 miRNAs were significantly downregulated in PCa compared with non-PCa tissues. We focused on the top four downregulated miRNAs (miR-187, miR-205, miR-222 and miR-31) to investigate their functional significance in PCa cells. Expression levels of these four miRNAs were validated in PCa specimens (15 PCa tissues and 17 non-PCa tissues) to confirm that they were significantly reduced in these PCa tissues. Gain-of-function analysis demonstrated that miR-222 and miR-31 inhibited cell proliferation, invasion and migration in PCa cell lines (PC3 and DU145), suggesting that miR-222 and miR-31 may act as tumor suppressors in PCa. Genome-wide gene expression analysis using miR-222 or miR-31 transfectants to identify the pathways they affect showed that many cancer-related genes are regulated by these miRNAs in PC3 cells. Identification and categorization of the molecular pathways regulated by tumor suppressive miRNAs could provide new information about the molecular mechanisms of PCa tumorigenesis.
British Journal of Cancer, 2017
Background: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. Methods: Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormonesensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). Results: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. Conclusions: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.
Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients
Oncotarget, 2014
We aimed to identify microRNA (miRNA) expression patterns in the serum of prostate cancer (CaP) patients that predict the risk of early treatment failure following radical prostatectomy (RP). Microarray and Q-RT-PCR analyses identified 43 miRNAs as differentiating disease stages within 14 prostate cell lines and reflectedpublically available patient data. 34 of these miRNA were detectable in the serum of CaP patients. Association with time to biochemical progression was examined in a cohort of CaP patients following RP. A greater than two-fold increase in hazard of biochemical progression associated with altered expression of miR-103, miR-125b and miR-222 (p<.0008) in the serum of CaP patients. Prediction models based on penalized regression analyses showed that the levels of the miRNAs and PSA together were better at detecting false positives than models without miRNAs, for similar level of sensitivity. Analyses of publically available data revealed significant and reciprocal re...
Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer
The Prostate, 2012
BACKGROUND. It is becoming increasingly evident that microRNAs (miRNAs) are associated with the development and progression of prostate cancer (PCa). METHODS. We examined the hypothesis that plasma miRNA levels can differentiate patients by aggressiveness in 82 PCa patients. Taqman based quantitative RT-PCR assays were performed to measure copy number of target miRNAs. RESULTS. miR-20a was significantly overexpressed in plasma from patients with stage 3 tumors compared to stage 2 or below (P ¼ 0.03). The expression levels for miR-20a and miR-21 were significantly increased in patients with high risk CAPRA scores (16,623 and 1,595 copies, respectively). Significantly increased miR-21 and miR-145 expression were observed for patients with intermediate or high risk D'Amico scores compared to patients with low risk scores (P ¼ 0.047 and 0.011, respectively). The relapse rates for CAPRA scores ranged from 1.9% for low risk to 9.5% for intermediate risk and to 22.2% for high risk patients (P ¼ 0.023). For D'Amico scores, the relapse rates ranged from 0.0% for low risk to 7.4% for intermediate risk and 17.6% for high risk patients (P ¼ 0.039). Expression of miR-21 and miR-221 significantly differentiated patients with intermediate risk from those with low risk CAPRA scores (AUC ¼ 0.801, P ¼ 0.002). Four miRNAs (miR-20a, miR-21, miR-145, and miR-221) could also distinguish high versus low risk in PCa patients by D'Amico score with an AUC of 0.824. CONCLUSIONS. These preliminary data suggest that altered plasma miRNAs may be useful predictors to distinguish PCa patients with varied aggressiveness. Further larger studies to validate this promising finding are warranted. Prostate # 2012 Wiley Periodicals, Inc.