Dataset Information

Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer.

ABSTRACT: Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S-EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S-EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S-EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S-EVs. A total of 543 small RNAs were found to be regulated by androgens including miR-19-3p and miR-361-5p. Analysis of S-EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration-resistant prostate cancer.

SUBMITTER: Martens-Uzunova ES

PROVIDER: S-EPMC8374107 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer.

Martens-Uzunova Elena S ES Kusuma Gina D GD Crucitta Stefania S Lim Hong Kiat HK Cooper Crystal C Riches James E JE Azad Arun A Ochiya Takahiro T Boyle Glen M GM Southey Melissa C MC Del Re Marzia M Lim Rebecca R Ramm Grant A GA Jenster Guido W GW Soekmadji Carolina C

Journal of extracellular vesicles 20210818 10

Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased ...[more]

PMID: 34434533

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Project description:Recently, much interest has been raised for the characterization of signaling molecules carried by extracellular vesicles (EVs), which are particularly enriched in milk (mEVs). Such interest is linked to the capability of EVs to cross biological barriers, resist acidification in the gastric environment, and exert modulation of the immune system, mainly through their microRNA (miRNA) content. We characterized the small-RNA cargo of colostrum EVs (colosEVs) and mEVs from Italian Mediterranean buffalo through next generation sequencing. Colostrum (first milking after birth) and milk (day 50 of lactation) were sampled from seven subjects from five farms. ColosEVs and mEVs were subjected to morphological characterization, followed by high-depth sequencing of small RNA libraries produced from total RNA. The main difference was the amount of EV in the two samples, with colostrum showing 10 to 100-fold higher content than milk. For both matrices, miRNA was the most abundant RNA species (95% for colosEVs and 96% for mEVs) and three lists were identified: colosEV-specific, mEV-specific and shared most expressed. Gene ontology (GO) enrichment analysis on miRNA targets highlighted many terms related to the epigenetic, transcriptional and translational regulations across the three lists, with a higher number of enriched terms for colosEV-specific miRNAs. Terms specific to colosEVs were related to "cell differentiation" and "microvillus assembly", while for mEV "cardiac and blood vessel development" and "mitochondria" emergerd. Immune modulation terms were found for both sample-specific miRNAs. Overall, both matrices carry a similar molecular message in terms of biological processes potentially modulated into receiving cells, but there is significant difference in the abundance, with colostrum containing much more EVs than milk. Moreover, colosEVs carry molecules involved in signal transduction, cell cycle and immune response, as for mEVs and EVs of other previously characterized species, but with a special enrichment for miRNAs with epigenetic regulation capacities. These beneficial characteristics of colosEVs and mEVs are essential for the calf and could also be exploited for the therapeutic purposes in humans, although further studies are necessary to measure the sanitization treatment impact on EV conservation, especially in buffalo where milk is consumed almost exclusively after processing.

Project description:BackgroundPleural Mesothelioma (PM) is a highly aggressive cancer, for which effective early detection remains a challenge due to limited screening options and low sensitivity of biomarkers discovered so far. While extracellular vesicles (EVs) have emerged as promising candidates for blood-based biomarkers, their role in PM has not been studied yet. In this study, we characterized the transcriptomic profile of EVs secreted by PM primary cells and explored their potential as a biomarker source for PM detection.MethodsWe collected cell culture supernatant from early-passage PM cell cultures derived from the pleural effusion of 4 PM patients. EVs were isolated from the supernatant using Qiagen exoEasy Maxi kit. RNA isolation from EVs was done using the mirVana PARIS kit. Finally, single-end RNA sequencing was done with Illumina Novaseq 6000.ResultsWe identified a range of RNA species expressed in EVs secreted by PM cells, including protein-coding RNA (80%), long non-coding RNA (13%), pseudogenes (4.5%), and short non-coding RNA (1.6%). We detected a subset of genes associated with the previously identified epithelioid (32 genes) and sarcomatoid molecular components (36 genes) in PM-EVs. To investigate whether these markers could serve as biomarkers for PM detection in blood, we compared the RNA content of PM-EVs with the cargo of EVs isolated from the plasma of healthy donors (publicly available data). Majority of upregulated genes in PM-EVs were protein-coding and long non-coding RNAs. Interestingly, 25 of them were the sarcomatoid and epithelioid marker genes. Finally, functional analysis revealed that the PM-EV RNA cargo was associated with Epithelial-Mesenchymal transition, glycolysis, and hypoxia.ConclusionsThis is the first study to characterize the transcriptomic profile of EVs secreted by PM primary cell cultures, demonstrating their potential as biomarker source for early detection. Further investigation of the functional role of PM-EVs will provide new insights into disease biology and therapeutic avenues.

Dataset Information

Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer.

Publications

Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer.

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