bims-prodis Biomed News
on Proteomics in disease
Issue of 2018–05–27
seven papers selected by
Nancy Gough, Bioserendipity
  1. Noninvasive diagnosis of endometriosis: Review of current peripheral blood and endometrial biomarkers.
  2. Profiling modifications for glioblastoma proteome using ultra-tolerant database search: Are the peptide mass shifts biologically relevant or chemically induced?
  3. Defining Host Responses during Systemic Bacterial Infection through Construction of a Murine Organ Proteome Atlas.
  4. Proteomic changes during adult stage in pre-optic, hypothalamus, hippocampus and pituitary regions of female rat brain following neonatal exposure to estradiol-17β.
  5. BRAF and MEK inhibitor therapy eliminates nestin expressing melanoma cells in human tumors.
  6. A functional glycoproteomics approach identifies CD13 as a novel E-selectin ligand in breast cancer.
  7. Altered Mitochondrial Acetylation Profiles in a Kainic Acid Model of Temporal Lobe Epilepsy.
  1. Best Pract Res Clin Obstet Gynaecol. 2018 Apr 13. pii: S1521-6934(18)30076-2. [Epub ahead of print]
    Noninvasive diagnosis of endometriosis: Review of current peripheral blood and endometrial biomarkers.
    Dorien F O, Idhaliz Flores, Etienne Waelkens, Thomas D'Hooghe.
      A noninvasive biomarker-based test could help shorten the diagnostic delay for endometriosis. The most investigated biomarker sources are peripheral blood and endometrium. Discovery of endometriosis biomarkers is often hypothesis-driven, i.e. when one or a few biomarkers are investigated based on their role in the disease pathogenesis. Alternatively, a hypothesis-generating approach has been followed using the "omics" technologies. A variety of biomarkers for endometriosis have been investigated, but no biomarker has been validated for clinical use. Many challenges lie ahead in the endometriosis biomarker field. In the future, harmonized collection and reporting methods should allow large-scale international collaboration for highly powered studies.
    Keywords:  Biomarker; Diagnosis; Endometriosis; Endometrium; Peripheral blood; Systems biology
    DOI:  https://doi.org/10.1016/j.bpobgyn.2018.04.001
  2. J Proteomics. 2018 May 17. pii: S1874-3919(18)30219-7. [Epub ahead of print]
    Profiling modifications for glioblastoma proteome using ultra-tolerant database search: Are the peptide mass shifts biologically relevant or chemically induced?
    Irina A Tarasova, Peter M Chumakov, Sergei A Moshkovskii, Mikhail V Gorshkov.
      Peptide mass shifts were profiled using ultra-tolerant database search strategy for shotgun proteomics data sets of human glioblastoma cell lines demonstrating strong response to the type I interferon (IFNα-2b) treatment. The main objective of this profiling was revealing the cell response to IFN treatment at the level of protein modifications. To achieve this objective, statistically significant changes in peptide mass shift profiles between IFN treated and untreated glioblastoma samples were analyzed. Detailed analysis of MS/MS spectra allowed further interpretation of the observed mass shifts and differentiation between post-translational and artifact modifications.
    SIGNIFICANCE: Malignant cells typically acquire increased sensitivity to viruses due to the deregulated antiviral mechanisms. Therefore, a viral therapy is considered as one of the promising approaches to treat cancer. However, recent studies have demonstrated that malignant cells can preserve intact antiviral mechanisms, e.g. interferon signaling, and develop resistance to virus infection in response to interferon treatment. Post translational modifications, e.g. tyrosine phosphorylation, are the interferon signaling drivers. Thus, comprehensive characterization of modifications is crucially important, yet, most challenging problem in cancer proteomics. Here, we report on the application of the recently introduced ultra-tolerant search strategy for profiling peptide modifications in the human glioblastoma cell lines demonstrating strong response to the type I interferon (IFNα-2b) treatment. The specific aim of the study was identification of statistically significant changes in peptide mass shift profiles between IFN treated and untreated glioblastoma samples, as well as determination of whether these shifts represent the biologically relevant modification.
    Keywords:  Chemical modifications; Glioblastoma; MSFragger; Open search profiling; PTMs
    DOI:  https://doi.org/10.1016/j.jprot.2018.05.010
  3. Cell Syst. 2018 May 23. pii: S2405-4712(18)30150-9. [Epub ahead of print]6(5): 579-592.e4
    Defining Host Responses during Systemic Bacterial Infection through Construction of a Murine Organ Proteome Atlas.
    John D Lapek, Robert H Mills, Jacob M Wozniak, Anaamika Campeau, Ronnie H Fang, Xiaoli Wei, Kirsten van de Groep, Araceli Perez-Lopez, Nina M van Sorge, Manuela Raffatellu, Rob Knight, Liangfang Zhang, David J Gonzalez.
      Group A Streptococcus (GAS) remains one of the top 10 deadliest human pathogens worldwide despite its sensitivity to penicillin. Although the most common GAS infection is pharyngitis (strep throat), it also causes life-threatening systemic infections. A series of complex networks between host and pathogen drive invasive infections, which have not been comprehensively mapped. Attempting to map these interactions, we examined organ-level protein dynamics using a mouse model of systemic GAS infection. We quantified over 11,000 proteins, defining organ-specific markers for all analyzed tissues. From this analysis, an atlas of dynamically regulated proteins and pathways was constructed. Through statistical methods, we narrowed organ-specific markers of infection to 34 from the defined atlas. We show these markers are trackable in blood of infected mice, and a subset has been observed in plasma samples from GAS-infected clinical patients. This proteomics-based strategy provides insight into host defense responses, establishes potentially useful targets for therapeutic intervention, and presents biomarkers for determining affected organs during bacterial infection.
    Keywords:  Orbitrap; S. pyogenes; Tandem Mass Tag; group A Streptococcus; multiplexed proteomics; systemic infection
    DOI:  https://doi.org/10.1016/j.cels.2018.04.010
  4. Gen Comp Endocrinol. 2018 May 16. pii: S0016-6480(17)30751-7. [Epub ahead of print]
    Proteomic changes during adult stage in pre-optic, hypothalamus, hippocampus and pituitary regions of female rat brain following neonatal exposure to estradiol-17β.
    Vijayakumar Govindaraj, Radhika Nagamangalam Shridharan, Addicam Jagannadha Rao.
      Although neonatal exposure to estrogen or estrogenic compounds results in irreversible changes in the brain function and reproductive abnormalities during adulthood but the underlying mechanisms are still largely unknown. The present study has attempted to compare the protein profiles of sexually dimorphic brain regions of adult female rats which were exposed to estradiol- 17β during neonatal period. The total proteins extracted from pre-optic area (POA), hypothalamus, hippocampus and pituitary of control and neonatally E2 treated female rats was subjected to 2D-SDS-PAGE and differentially expressed proteins were identified by MALDI TOF/TOF-MS. Our results revealed that a total of 21 protein spots which were identified as differentially expressed in all the four regions analyzed; the differential expression was further validated by RT-PCR and western blotting. The differentially expressed proteins such as 14-3-3 zeta/delta (POA), LMNA (hippocampus), Axin2 (hypothalamus), Syntaxin-7 (hippocampus), prolactin and somatotropin (pituitary) which have very important functions in the process of neuronal differentiation, migration, axon outgrowth, formation of dendritic spine density and synaptic plasticity and memory have not been previously reported in association with neonatal estrogen exposure. The affected brain functions are very important for the establishment of sex specific brain morphology and behavior. Our results suggest that the differentially expressed proteins may play an important role in irreversible changes in the brain function as well as reproductive abnormalities observed in the female rats during adulthood.
    Keywords:  Hippocampus; Hypothalamus; Neonatal estradiol-17β exposure; Pituitary; Pre-optic area; Proteomics; Two-dimensional electrophoresis
    DOI:  https://doi.org/10.1016/j.ygcen.2018.05.005
  5. Pigment Cell Melanoma Res. 2018 May 19.
    BRAF and MEK inhibitor therapy eliminates nestin expressing melanoma cells in human tumors.
    Deon B Doxie, Allison R Greenplate, Jocelyn S Gandelman, Kirsten E Diggins, Caroline E Roe, Kimberly B Dahlman, Jeffrey A Sosman, Mark C Kelley, Jonathan M Irish.
      Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAFV600mut melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin expressing melanoma cells. Melanoma cells subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100β+ melanoma cells. This quantitative single cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Melanoma; kinase inhibitors; mass cytometry; single cell; targeted therapy
    DOI:  https://doi.org/10.1111/pcmr.12712
  6. Biochim Biophys Acta. 2018 May 16. pii: S0304-4165(18)30145-4. [Epub ahead of print]
    A functional glycoproteomics approach identifies CD13 as a novel E-selectin ligand in breast cancer.
    M A Carrascal, M Silva, J A Ferreira, R Azevedo, D Ferreira, A M N Silva, D Ligeiro, L L Santos, R Sackstein, P A Videira.
       BACKGROUND: The glycan moieties sialyl-Lewis-X and/or -A (sLeX/A) are the primary ligands for E-selectin, regulating subsequent tumor cell extravasation into distant organs. However, the nature of the glycoprotein scaffolds displaying these glycans in breast cancer remains unclear and constitutes the focus of the present investigation.
    METHODS: We isolated glycoproteins that bind E-selectin from the CF1_T breast cancer cell line, derived from a patient with ductal carcinoma. Proteins were identified using bottom-up proteomics approach by nanoLC-orbitrap LTQ-MS/MS. Data were curated using bioinformatics tools to highlight clinically relevant glycoproteins, which were validated by flow cytometry, Western blot, immunohistochemistry and in-situ proximity ligation assays in clinical samples.
    RESULTS: We observed that the CF1_T cell line expressed sLeX, but not sLeA and the E-selectin reactivity was mainly on N-glycans. MS and bioinformatics analysis of the targeted glycoproteins, when narrowed down to the most clinically relevant species in breast cancer, identified as key E-selectin ligands, CD44 glycoprotein (HCELL) and also CD13. Additionally, the co-expression of sLeX-CD44 and sLeX-CD13 was confirmed in clinical breast cancer tissue samples.
    CONCLUSIONS: Both CD44 and CD13 glycoforms display sLeX in breast cancer and bind E-selectin, suggesting a key role in metastasis development. Such observations provide a novel molecular rationale for developing targeted therapeutics.
    GENERAL SIGNIFICANCE: While HCELL expression in breast cancer has been previously reported, this is the first study indicating that CD13 functions as an E-selectin ligand in breast cancer. This observation supports previous associations of CD13 with metastasis and draws attention to this glycoprotein as an anti-cancer target.
    Keywords:  Breast cancer; CD13; CD44; E-selectin ligand; HCELL; sLe(X)
    DOI:  https://doi.org/10.1016/j.bbagen.2018.05.013
  7. Free Radic Biol Med. 2018 May 17. pii: S0891-5849(18)30887-6. [Epub ahead of print]
    Altered Mitochondrial Acetylation Profiles in a Kainic Acid Model of Temporal Lobe Epilepsy.
    Lindsey B Gano, Li-Ping Liang, Kristen Ryan, Cole R Michel, Joe Gomez, Athanassios Vassilopoulos, Nichole Reisdorph, Kristofer S Fritz, Manisha Patel.
      Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48hours, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy.
    Keywords:  SIRT3; acetylation; epilepsy; mass spectrometry; mitochondria; proteomics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2018.05.063
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