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MicroRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.

ABSTRACT: Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostatic hyperplasia, and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in prostate cancer clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a prostate cancer cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial-mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathologic grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising prostate cancer biomarker with diagnostic potential that can predict disease aggressiveness.Significance: Dysregulation of exosomal miRNAs in aggressive prostate cancer leads to alteration of key signaling pathways associated with metastatic prostate cancer. Cancer Res; 78(7); 1833-44. ©2018 AACR.

SUBMITTER: Bhagirath D

PROVIDER: S-EPMC5890910 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.

Bhagirath Divya D Yang Thao Ly TL Bucay Nathan N Sekhon Kirandeep K Majid Shahana S Shahryari Varahram V Dahiya Rajvir R Tanaka Yuichiro Y Saini Sharanjot S

Cancer research 20180201 7

Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostati ...[more]

PMID: 29437039

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Project description:IntroductionProstate cancer (PC) is one of the most frequently diagnosed cancers in males. MiR-153, as a member of the microRNA (miRNA) family, plays an important role in PC. This study aims to explore the expression and possible molecular mechanisms of the miR-153 action.MethodsFormalin-fixed paraffin-embedded (FFPE) tissues were collected from prostatectomy specimens of 29 metastatic and 32 initial stage PC patients. Expression levels of miR-153 were measured using real-time reverse transcription polymerase chain reaction (qRT-PCR). 2-ΔΔCT method was used for quantitative gene expression assessment. The candidate target genes for miR-153 were predicted by TargetScan. Mutations in target genes of miR-153 were identified using exome sequencing. Protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the potential molecular mechanisms of miR-153 in PC.ResultsMiR-153 was significantly up-regulated in PC tissues compared to non-cancerous tissues. The analysis of correlation between the expression level of miR-153 and clinicopathological factors revealed a statistically significant correlation with the stage of the tumor process according to tumor, node, metastasis (TNM) staging system (p = 0.0256). ROC curve analysis was used to evaluate the predictive ability of miR-153 for metastasis development and it revealed miR-153 as a potential prognostic marker (AUC = 0.85; 95%CI 0.75-0.95; sensitivity = 0.72, specificity = 0.86)). According to logistic regression model the high expression of miR-153 increased the risk of metastasis development (odds ratios = 3.14, 95% CI 1.62-8.49; p-value = 0.006). Whole exome sequencing revealed nonsynonymous somatic mutations in collagen type IV alpha 1 (COL4A1), collagen type IV alpha 3 (COL4A3), forkhead box protein O1 (FOXO1), 2-hydroxyacyl-CoA lyase 1 (HACL1), hypoxia-inducible factor 1-alpha (HIF-1A), and nidogen 2 (NID2) genes. Moreover, KEGG analysis revealed that the extracellular matrix-receptor (ECM-receptor) interaction pathway is mainly involved in PC.ConclusionMiR-153 is up-regulated in PC tissues and may play an important role in aggressive PC by targeting potential target genes.

Project description:PURPOSE:Novel biomarkers for the diagnosis of prostate cancer (PCa) are urgently required. Increasing evidence suggests that exosomal microRNAs (miRNAs or miRs) in serum may be potential noninvasive biomarkers for certain diseases. The objective of the present study was to investigate and assess whether exosomal miR-141 is an effective biomarker for human PCa. METHODS:In the present study, exosomes were isolated from the serum of patients with PCa, patients with benign prostate hyperplasia (BPH), and healthy volunteers. The total RNA was extracted from the exosomes and the level of miR-141 was analyzed by quantitative reverse transcription-polymerase chain reaction. The expression levels of miR-141 were compared between the whole serum and the serum exosomes of the three groups. Subsequently, the relevance of the exosomal expression of miR-141 to the clinicopathological factors in PCa was investigated. RESULTS:The expression of miR-141 was higher in exosomes compared with whole serum (control group, P=0.0003; BPH group, P=0.0016; PCa group, P<0.0001). The level of serum exosomal miR-141 was significantly higher in the patients with PCa compared with the patients with BPH and the healthy controls (3.85-fold, P=0.0007 and 4.06-fold, P=0.0005, respectively). In addition, the expression levels were significantly higher in metastatic PCa compared with localized PCa (P<0.0001). Receiver-operating characteristic curve revealed that the serum exosomal miR-141 yielded an area under the curve of 0.8694, with 80% sensitivity and 87.1% specificity in discriminating patients with metastatic PCa from the patients with localized PCa. CONCLUSION:Serum exosomes may serve as a more suitable material compared with the whole serum for measuring circulating miR-141 levels in patients with PCa. Exosomal miR-141 is upregulated in the serum from patients with PCa compared with patients with BPH or the healthy volunteers, and it may be a useful potential biomarker for the diagnosis of metastatic PCa.

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MicroRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.

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microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.

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