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Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples.

ABSTRACT: There is a compelling clinical imperative to identify discerning molecular biomarkers of hepatic disease in order to inform the diagnosis, prognosis and treatment.We have investigated the proteome of urinary vesicles present in urine samples obtained from experimental models for the study of liver injury, as an approach for identifying potential biomarkers for hepatic disease.The biochemical and proteomic characterization of highly purified exosome-like urinary vesicles has identified 28 proteins previously unreported in these vesicles, and many that have been previously associated with diseases, such as the prion-related protein. Furthermore, in urine samples from D-galactosamine-treated rats, a well-characterized experimental model for acute liver injury, we have detected a severe reduction in some proteins that normally are clearly detected in urinary vesicles. Finally, differential protein content on urinary vesicles from a mouse model for chronic liver injury has been also identified.Our results argue positively that urinary vesicles could be a source for identifying non-invasive biomarkers of liver injury. We proposed some proteins such as Cd26, Cd81, Slc3A1 and Cd10 that have been found to be differentially expressed in urinary vesicles from some of the analyzed models as potential biomarkers for liver injury.

SUBMITTER: Conde-Vancells J

PROVIDER: S-EPMC2882112 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples.

Conde-Vancells Javier J Rodriguez-Suarez Eva E Gonzalez Esperanza E Berisa Agustin A Gil David D Embade Nieves N Valle Mikel M Luka Zigmund Z Elortza Felix F Wagner Conrad C Lu Shelly C SC Mato Jose M JM Falcon-Perez M M

Proteomics. Clinical applications 20100401 4

<h4>Purpose</h4>There is a compelling clinical imperative to identify discerning molecular biomarkers of hepatic disease in order to inform the diagnosis, prognosis and treatment.<h4>Experimental design</h4>We have investigated the proteome of urinary vesicles present in urine samples obtained from experimental models for the study of liver injury, as an approach for identifying potential biomarkers for hepatic disease.<h4>Results</h4>The biochemical and proteomic characterization of highly puri ...[more]

PMID: 20535238

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Project description:BackgroundExosomes are involved in cell-to-cell communication, neovascularization, cancer metastasis, and drug resistance, which all play an important role in the occurrence and progression of hepatocellular carcinoma (HCC). Because there are few mechanistic studies about the function of exosomes in HCC, the goals of this study were to identify exosome-related genes in HCC, to establish a reliable prognostic model for HCC, and to explore underlying mechanisms.MethodsThe exoRBase and The Cancer Genome Atlas (TCGA) databases were used to analyze differentially expressed genes (DEGs). Cox regression and least absolute shrinkage and selection operator analyses were used to identify DEGs closely related to the overall survival of patients with HCC. An exosome-related prognostic model was then constructed in TCGA and validated in the International Cancer Genome Consortium database. A nomogram was developed to predict survival. CIBERSORT was used to estimate the abundance of different types of immune cells. Immunotherapy-related DEGs were used to predict the effect of immunotherapy.ResultsForty-eight exosome-related DEGs were obtained; of them, five [exportin 1 (XPO1), lysosomal thiol reductase (IFI30), F-box protein 16 (FBXO16), calmodulin 1 (CALM1), MORC family CW-type zinc finger 3 (MORC3)] were selected to construct a predictive model. Patients with HCC were then divided into low- and high-risk groups using the best cut-off value, as determined by the X-tile software. Prognosis was significantly poorer in the high-risk than in the low-risk group (P=0.009; hazard ratio =2.65). Features related to exosomes were found to positively regulate immune response. Further analysis showed a higher risk score was associated with higher expression of immune checkpoint molecules, including programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell Ig and ITIM domain (TIGIT), and indoleamine-2,3-dioxygenase 1 (IDO1).ConclusionsThis study has identified a novel signature based on exosome-related genes that has potential as a prognostic biomarker for HCC. Our research provides an immunological perspective for the development of precision treatment for HCC.

Project description:Noninvasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflected coronary artery disease with high accuracy. The aim of the current study is to use urine proteomics in ApoE(-/-) mice to discover proteins with pathophysiological roles in atherogenesis and to identify urinary polypeptide patterns reflecting early stages of atherosclerosis. Urine of ApoE(-/-) mice either on high fat diet (HFD) or chow diet was collected over 12 weeks; urine of wild type mice on HFD was used to exclude diet-related proteome changes. Capillary electrophoresis coupled to mass spectrometry (CE-MS) of samples identified 16 polypeptides specific for ApoE(-/-) mice on HFD. In a blinded test set, these polypeptides allowed identification of atherosclerosis at a sensitivity of 90% and specificity of 100%, as well as monitoring of disease progression. Sequencing of the discovered polypeptides identified fragments of ?(1)-antitrypsin, epidermal growth factor (EGF), kidney androgen-regulated protein, and collagen. Using immunohistochemistry, ?(1)-antitrypsin, EGF, and collagen type I were shown to be highly expressed in atherosclerotic plaques of ApoE(-/-) mice on HFD. Urinary excretion levels of collagen and ?(1)-antitrypsin fragments also significantly correlated with intraplaque collagen and ?(1)-antitrypsin content, mirroring plaque protein expression in the urine proteome. To provide further confirmation that the newly identified proteins are relevant in humans, the presence of collagen type I, ?(1)-antitrypsin, and EGF was also confirmed in human atherosclerotic disease. Urine proteome analysis in mice exemplifies the potential of a novel multimarker approach for the noninvasive detection of atherosclerosis and monitoring of disease progression. Furthermore, this approach represents a novel discovery tool for the identification of proteins relevant in murine and human atherosclerosis and thus also defines potential novel therapeutic targets.

Dataset Information

Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples.

Publications

Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples.

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