Dataset Information

Human Blood Serum LC-MS/MS - Serological epithelial component proteins identify intestinal complications in Crohn's Disease

ABSTRACT: Quantitative proteome profiling was performed on Inflammatory (ICD), stricturing and fistulizing Crohn's Disease serums using label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

INSTRUMENT(S): LTQ FT

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood Serum

DISEASE(S): Crohn's Disease

SUBMITTER: Yunki Yau

LAB HEAD: Mark Raftery

PROVIDER: PXD001821 | Pride | 2017-05-15

REPOSITORIES: Pride

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Publications

Serological Epithelial Component Proteins Identify Intestinal Complications in Crohn's Disease.

Yau Yunki Y YY Leong Rupert W L RWL Pudipeddi Aviv A Redmond Diane D Wasinger Valerie C VC

Molecular & cellular proteomics : MCP 20170510 7

Crohn's Disease (CD) is a relapsing inflammation of the gastrointestinal tract that affects a young working age population and is increasing in developing countries. Half of all sufferers will experience stricturing or fistulizing intestinal complications that require extensive surgical interventions and neither genes nor clinical risk factors can predict this debilitating natural history. We applied discovery and verification phase studies as part of an NCI-FDA modeled biomarker pipeline to ide ...[more]

PMID: 28490445

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Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

Project description:Crohn's Disease (CD) is a relapsing inflammation of the gastrointestinal tract that affects a young working age population and is increasing in developing countries. Half of all sufferers will experience stricturing or fistulizing intestinal complications that require extensive surgical interventions and neither genes nor clinical risk factors can predict this debilitating natural history. We applied discovery and verification phase studies as part of an NCI-FDA modeled biomarker pipeline to identify differences in the low-mass (<25kDa) blood-serum proteome between CD behavioral phenotypes. A significant enrichment of epithelial component proteins was identified in CD patients with intestinal complications using quantitative proteomic profiling with label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). DAVID 6.7 (NIH) was used for functional annotation analysis of detected proteins and immunoblotting and multiple reaction monitoring (MRM) to verify a priori findings in a secondary independent cohort of complicated CD (CCD), uncomplicated inflammatory CD (ICD), Th1/17 pathway inflammation controls (rheumatoid arthritis), inflammatory bowel disease controls (ulcerative colitis), and healthy controls. Seventy-six high-confidence serum proteins were modulated in CCD versus ICD by LC-MS/MS (p < 0.05, FDR q<0.01), annotating to pathways of epithelial barrier homeostasis (p < 0.01). In verification phase, a putative serology panel developed from discovery proteomics data consisting of desmoglein-1, desmoplakin, and fatty acid-binding protein 5 (FABP5) distinguished CCD from all other groups (p = 0.041) and discriminated complication in CD (70% sensitivity and 72.5% specificity at score ≥1.907, AUC = 0.777, p = 0.007). An MRM assay secondarily confirmed increased FABP5 levels in CCD (p < 0.001). In a longitudinal subanalysis-cohort, FABP5 levels were stable over a two-month period with no behavioral changes (p = 0.099). These studies along the biomarker development pipeline provide substantial proof-of-principle that a blood test can be developed specific to transmural intestinal injury. Data are available via the PRIDE proteomics data repository under identifier PXD001821 and PeptideAtlas with identifier PASS00661.

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