Exosomal microRNA profiling to identify hypoxia-related biomarkers in prostate cancer.

Gati K Panigrahi,Rajeev Vibhakar,Lance D Miller,Zakaria Y Abd Elmageed,Rajesh Agarwal,Sujatha Venkataraman,Gagan Deep,Diane Birks,Anand Ramteke,Hamdy E Abouzeid Ali,Chapla Agarwal

doi:10.18632/oncotarget.24532

Abstract

Hypoxia and expression of hypoxia-related biomarkers are associated with disease progression and treatment failure in prostate cancer (PCa). We have reported that exosomes (nanovesicles of 30-150 nm in diameter) secreted by human PCa cells under hypoxia promote invasiveness and stemness in naïve PCa cells. Here, we identified the unique microRNAs (miRNAs) loaded in exosomes secreted by PCa cells under hypoxia. Using TaqMan® array microRNA cards, we analyzed the miRNA profile in exosomes secreted by human PCa LNCaP cells under hypoxic (ExoHypoxic) and normoxic (ExoNormoxic) conditions. We identified 292 miRNAs loaded in both ExoHypoxic and ExoNormoxic. The top 11 miRNAs with significantly higher level in ExoHypoxic compared to ExoNormoxic were miR-517a, miR-204, miR-885, miR-143, miR-335, miR-127, miR-542, miR-433, miR-451, miR-92a and miR-181a; and top nine miRNA with significantly lower expression level in ExoHypoxic compared to ExoNormoxic were miR-521, miR-27a, miR-324, miR-579, miR-502, miR-222, miR-135b, miR-146a and miR-491. Importantly, the two differentially expressed miRNAs miR-885 (increased expression) and miR-521 (decreased expression) showed similar expression pattern in exosomes isolated from the serum of PCa patients compared to healthy individuals. Additionally, miR-204 and miR-222 displayed correlated expression patterns in prostate tumors (Pearson R = 0.66, p < 0.0001) by The Cancer Genome Atlas (TCGA) prostate adenocarcinoma (PRAD) genomic dataset analysis. Overall, the present study identified unique miRNAs with differential expression in exosomes secreted from hypoxic PCa cells and suggests their potential usefulness as a biomarker of hypoxia in PCa patients.

Highlights

Prostate cancer (PCa) is the most common noncutaneous cancer among men worldwide and a leading cause of cancer-related death in the United States and in Europe [1]
We have reported that exosomes secreted by human prostate cancer (PCa) cells under hypoxia promote invasiveness and stemness in naïve PCa cells
The present study identified unique miRNAs with differential expression in exosomes secreted from hypoxic PCa cells and suggests their potential usefulness as a biomarker of hypoxia in PCa patients

Summary

Introduction

Prostate cancer (PCa) is the most common noncutaneous cancer among men worldwide and a leading cause of cancer-related death in the United States and in Europe [1]. The poor association between disease state and PSA levels sometimes leads to needless diagnoses and overtreatment of indolent PCa [2]. Apart from proteins and messenger RNAs (mRNAs), which have shown utility in several clinical scenarios, there is growing interest regarding the utility of microRNAs (miRNAs) as PCa biomarkers. MiRNAs are a group of small (

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