Mass spectrometry-based expression profiling of clinical prostate cancer

UC Davis Genome Center, Department of Pharmacology and Toxicology, University of California Davis School of Medicine, Davis, CA 95616, USA.
Molecular &amp Cellular Proteomics (Impact Factor: 6.56). 05/2005; 4(4):545-54. DOI: 10.1074/mcp.R500008-MCP200
Source: PubMed


The maturation of MS technologies has provided a rich opportunity to interrogate protein expression patterns in normal and disease states by applying expression protein profiling methods. Major goals of this research strategy include the identification of protein biomarkers that demarcate normal and disease populations, and the identification of therapeutic biomarkers for the treatment of diseases such as cancer (Celis, J. E., and Gromov, P. (2003) Proteomics in translational cancer research: Toward an integrated approach. Cancer Cell 3, 9-151). Prostate cancer is one disease that would greatly benefit from implementing MS-based expression profiling methods because of the need to stratify the disease based on molecular markers. In this review, we will summarize the current MS-based methods to identify and validate biomarkers in human prostate cancer. Lastly, we propose a reverse proteomic approach implementing a quantitative MS research strategy to identify and quantify biomarkers implicated in prostate cancer development. With this approach, the absolute levels of prostate cancer biomarkers will be identified and quantified in normal and diseased samples by measuring the levels of native peptide biomarkers in relation to a chemically identical but isotopically labeled reference peptide. Ultimately, a centralized prostate cancer peptide biomarker expression database could function as a repository for the identification, quantification, and validation of protein biomarker(s) during prostate cancer progression in men.

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Available from: Michael E Wright, Jul 28, 2015
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    • "One protein, Tamm-Horsfall Protein (Uromodulin), was common to all three groups. Uromodulin is one of the most abundant proteins in urine 33, 34, 35 and normally runs as a monomer around 68kDa on denaturing gels. It is therefore likely that uromodulin, at least in part, formed the band that was observed near 66kDa in many of the samples from this study. "
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    ABSTRACT: Globally, Prostate cancer (PCa) is the most frequently occurring non-cutaneous cancer, and is the second highest cause of cancer mortality in men. Serum prostate specific antigen (PSA) has been the standard in PCa screening since its approval by the American Food & Drug Administration (FDA) in 1994. Currently, PSA is used as an indicator for PCa - patients with a serum PSA level above 4ng/mL will often undergo prostate biopsy to confirm cancer. Unfortunately fewer than ~30% of these men will biopsy positive for cancer, meaning that the majority of men undergo invasive biopsy with little benefit. Despite PSA's notoriously poor specificity (33%), there is still a significant lack of credible alternatives. Therefore an ideal biomarker that can specifically detect PCa at an early stage is urgently required. The aim of this study was to investigate the potential of using deregulation of urinary proteins in order to detect Prostate Cancer (PCa) among Benign Prostatic Hyperplasia (BPH). To identify the protein signatures specific for PCa, protein expression profiling of 8 PCa patients, 12 BPH patients and 10 healthy males was carried out using LC-MS/MS. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant the down-regulation of Fibronectin and TP53INP2 was a characteristic event among PCa patients. Fibronectin mRNA down-regulation, was identified as offering improved specificity (50%) over PSA, albeit with a slightly lower although still acceptable sensitivity (75%) for detecting PCa. As for TP53INP2 on the other hand, its down-regulation was moderately sensitive (75%), identifying many patients with PCa, but was entirely non-specific (7%), designating many of the benign samples as malignant and being unable to accurately identify more than one negative.
    Journal of Cancer 01/2014; 5(2):103-14. DOI:10.7150/jca.6890 · 3.27 Impact Factor
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    • "The simultaneous analysis of quantity as well as quality of thousands of proteins (modified or unmodified) with 2-DE could support various approaches to study cancer biology. Furthermore, 2-DE coupled with nano liquid chromatographic mass spectrometry (nLC-MS) is an effective technique in clinical proteomics to explore complex protein mixtures [28], [29]. As outlined above, understanding the HIF-1-dependent protein dynamics in the nucleus holds promise to improve therapy efficacy of solid gastric cancer. "
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    ABSTRACT: The majority of gastric cancers are diagnosed at advanced stages, characterized by robust therapy resistance. The oncoprotein hypoxia-inducible factor 1 (HIF-1) is associated with therapy resistance, partly via activation of the DNA damage response (DDR). We have noted a robust ability of gastric cancer cells to functionally compensate the loss of HIF-1 in vitro. The purpose of this study was to identify molecular pathways that underlie this compensation. We performed two dimensional gel electrophoresis (2DE) to compare the nuclear proteome of wildtype and HIF-1-deficient gastric cancer cells. Differently expressed protein spots were identified via mass spectrometry (MS). After bioinformatic evaluation, functional validation of selected identified pathways was performed. 2DE displayed a total of 2523 protein spots, from which 87 were identified as regulated by HIF-1. 70 of the identified spots were different proteins and 17 were isoforms. Bioinformatic analyses revealed that a significant amount of the identified proteins were related to cellular survival pathways. Specifically, members of the proteasome pathway were found upregulated upon loss of HIF-1. Combined inhibition of HIF-1 and the proteasome inflicted significant DNA damage, supporting the hypothesis that the proteasome is of functional importance to compensate the loss of HIF-1. Our data show robust and functional changes of the nuclear proteome upon inactivation of the HIF-1 oncoprotein in gastric cancer cells. We propose that 2DE-MS represents a useful tool to functionally dissect resistance mechanisms to targeted therapy and to identify novel targets for antiproliferative combination therapy.
    PROTEOMICS - CLINICAL APPLICATIONS 12/2013; DOI:10.1002/prca.201300056 · 2.96 Impact Factor
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    • "Tissue proteomics is considered a logical first step for the novel discovery of tumourderived proteins as they exist in higher concentrations due to their more direct proximity to cancer cells (Cravatt et al., 2007; Hanash et al., 2008; Joyce, 2005; Mueller & Fusenig, 2004; Wright et al., 2005). However, it is not well understood how protein expression in tissues reflect measurable levels in the serum or plasma that would allow the monitoring of the pathophysiological status of respective tissue (Anderson, 2010; Barelli, Crettaz, Thadikkaran, Rubin, & Tissot, 2007; Farrah et al., 2011; Hanash et al., 2008; Issaq, Xiao, & Veenstra, 2007). "

    Biomarker, 03/2012; , ISBN: 978-953-51-0577-0
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