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MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

ABSTRACT: Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM) versus non-brain metastatic (non-BM) cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70W, MDA-MB-231BR, and circulating tumor cell brain metastasis-selected markers (CTC1BMSM) variants, and compared them with parental non-BM MeWo, MDA-MB-231P and CTC1P cells, respectively. By performing microRNA PCR array we identified one up-regulated (miR-210) and two down-regulated miRNAs (miR-19a and miR-29c) in BM versus non-BM exosomes. Second, we analyzed the proteomic content of cells and exosomes isolated from these six cell lines, and detected high expression of proteins implicated in cell communication, cell cycle, and in key cancer invasion and metastasis pathways. Third, we show that BM cell-derived exosomes can be internalized by non-BM cells and that they effectively transport their cargo into cells, resulting in increased cell adhesive and invasive potencies. These results provide a strong rationale for additional investigations of exosomal proteins and miRNAs towards more profound understandings of exosome roles in brain metastasis biogenesis, and for the discovery and application of non-invasive biomarkers for new therapies combating brain metastasis.

SUBMITTER: Camacho L

PROVIDER: S-EPMC3774795 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

Camacho Laura L Guerrero Paola P Marchetti Dario D

PloS one 20130916 9

Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM) versus non-brain metastatic (non-BM) cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70 ...[more]

PMID: 24066071

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Project description:BackgroundMetastases within liver or the brain are the most common causes of mortality from lung cancer (LC). Predicting liver or brain metastases before having evidence from imaging of the tumors is challenging but important for early patient intervention. According to mounting evidence, exosomes circulating within blood may facilitate cancer spread by transporting certain proteins for target cells.MethodsUsing liquid chromatography-MS/MS, we investigated the plasma exosomes' proteomic profiles derived from 42 metastatic LC patients [16 solitary liver metastasis (LM), together with 26 solitary brain metastasis (BM)] and 25 local advanced (LA) lung cancer cases without metastasis, together with five healthy controls (HC), assessing the LM and BM pathogenesis and find potential novel organ-designated proteomic biomarkers. Using ELISA assay, we verified the expression levels of three plasma exosomal protein biomarkers in 110 LC patients, including 40 solitary LM, 32 solitary BM and 38 LA, and 25 HC.ResultsIn total, 143 and 120 differentially expressed exosome-based proteins (DEEPs) were found to be dysregulated in LM and BM of lung cancer (LM-DEEPs, BM-DEEPs), compared for LA lung cancer samples, respectively. The bioinformatics analyses indicated the heterogeneity and homogeneity in LM-DEEPs and BM-DEEPs. They were primarily engaged within proteomic triggering cascade, ECM-receptor interaction, and the collagen-containing extracellular matrix. Regarding heterogeneity, LM-DEEPs primarily consisted of proteoglycans, lipoprotein, integrin, and heat shock protein, whereas the BM-DEEPs consisted of calcium-dependent/S100 proteins. Furthermore, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)-plasma-stemming exosome proteomics showed heterogeneity, which helped to explain some of the differences between SCLC and NSCLC's metastatic features. We also found that SELL and MUC5B could be used as diagnostic markers of BM, while APOH, CD81, and CCT5 could help diagnose LM in LC patients. Additionally, we demonstrated in a validation cohort that MUC5B and SELL could serve as biomarkers for diagnosing BM, and APOH could be a novel potential diagnostic biomarker of LM.ConclusionWe presented the comprehensive and comparative plasma-stemming exosomes' proteomic profiles from cases of LC who had isolated liver and brain metastases for the first time. We also suggested several possible biomarkers and pathogenic pathways that might be a great starting point for future research on LC metastasis.

Project description:Purpose:Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. Exosomes are membrane-enclosed extracellular vesicles, and exosomal RNA can be a biomarker for cancer diagnosis and prognosis in RCC patients. We aim to identify differences in miRNA expression profiles in peripheral blood exosomes between RCC patients and healthy subjects as well as to investigate novel markers of RCC. Methods:We performed exosomal miRNA sequencing of plasma samples obtained from five RCC patients and five control subjects, subsequently 22 RCC patients and 16 control subjects were investigated using qPCR to confirm the differential miRNA which from plasma exosomal RNA sequencing. ROC curves were constructed to assess the diagnostic accuracy of exosomal miRNAs as diagnostic biomarkers of RCC. Results:Exosomes were isolated with the exoeasy maxi kit and confirmed using TEM and NTA. They have a spherical structure with a diameter of approximately 40-180 nm. The exosomal miRNA sequence results showed that a total of 2357 miRNAs were detected, and 245 miRNAs were differentially expressed between RCC patients and healthy controls (p<0.001, average counts >5, log|fc|>1). Further analysis revealing that, versus the control, 17 miRNAs are up-regulated and 5 miRNAs are down-regulated under selection conditions with average miRNAs counts >100. qPCR was performed using 38 subjects-the results showed that the expression levels of hsa-mir-149-3p and hsa-mir-424-3p were upregulated; the expression levels of hsa-mir-92a-1-5p were significantly downregulated in the plasma exosomes of RCC. For diagnosis of RCC, the AUC of hsa-mir-92a-1-5p, hsa-mir-149-3p and hsa-mir-424-3p was 0.8324, 0.7188 and 0.7727, with the sensitivity of 0.875, 0.750 and 0.750, and the specificity of 0.773,0.727 and 0.818, respectively, at the best cutoff value. Conclusion:Our study revealed that the expression levels of hsa-mir-92a-1-5p, hsa-mir-149-3p and hsa-mir-424-3p were significantly abnormal in RCC patients, which may be novel biomarkers for RCC diagnosis.

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MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

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MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

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