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@ARTICLE{Subedi:277291,
      author       = {P. Subedi and K. Huber and C. Sterr and A. Dietz and L.
                      Strasser and F. Kaestle and S. M. Hauck and L. Duchrow and
                      C. Aldrian$^*$ and E. B. Monroy Ordonez$^*$ and B. Luka and
                      A. R. Thomsen$^*$ and M. Henke$^*$ and M. Gomolka and U.
                      Rößler and O. Azimzadeh and S. Moertl and S. Hornhardt},
      title        = {{T}owards unravelling biological mechanisms behind
                      radiation-induced oral mucositis via mass spectrometry-based
                      proteomics.},
      journal      = {Frontiers in oncology},
      volume       = {13},
      issn         = {2234-943X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2023-01320},
      pages        = {1180642},
      year         = {2023},
      abstract     = {Head and neck cancer (HNC) accounts for almost 890,000 new
                      cases per year. Radiotherapy (RT) is used to treat the
                      majority of these patients. A common side-effect of RT is
                      the onset of oral mucositis, which decreases the quality of
                      life and represents the major dose-limiting factor in RT. To
                      understand the origin of oral mucositis, the biological
                      mechanisms post-ionizing radiation (IR) need to be
                      clarified. Such knowledge is valuable to develop new
                      treatment targets for oral mucositis and markers for the
                      early identification of 'at-risk' patients.Primary
                      keratinocytes from healthy volunteers were biopsied,
                      irradiated in vitro (0 and 6 Gy), and subjected to mass
                      spectrometry-based analyses 96 h after irradiation.
                      Web-based tools were used to predict triggered biological
                      pathways. The results were validated in the OKF6 cell
                      culture model. Immunoblotting and mRNA validation was
                      performed and cytokines present in cell culture media
                      post-IR were quantified.Mass spectrometry-based proteomics
                      identified 5879 proteins in primary keratinocytes and 4597
                      proteins in OKF6 cells. Amongst them, 212 proteins in
                      primary keratinocytes and 169 proteins in OKF6 cells were
                      differentially abundant 96 h after 6 Gy irradiation compared
                      to sham-irradiated controls. In silico pathway enrichment
                      analysis predicted interferon (IFN) response and DNA strand
                      elongation pathways as mostly affected pathways in both cell
                      systems. Immunoblot validations showed a decrease in
                      minichromosome maintenance (MCM) complex proteins 2-7 and an
                      increase in IFN-associated proteins STAT1 and ISG15. In line
                      with affected IFN signalling, mRNA levels of IFNβ and
                      interleukin 6 (IL-6) increased significantly following
                      irradiation and also levels of secreted IL-1β, IL-6, IP-10,
                      and ISG15 were elevated.This study has investigated
                      biological mechanisms in keratinocytes post-in vitro
                      ionizing radiation. A common radiation signature in
                      keratinocytes was identified. The role of IFN response in
                      keratinocytes along with increased levels of
                      pro-inflammatory cytokines and proteins could hint towards a
                      possible mechanism for oral mucositis.},
      keywords     = {MCM complex (Other) / STAT phosphorylation (Other) /
                      biomarker (Other) / interferon response (Other) /
                      keratinocytes (Other) / mass spectrometry-based proteomics
                      (Other) / radiotherapy (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37384298},
      pmc          = {pmc:PMC10298177},
      doi          = {10.3389/fonc.2023.1180642},
      url          = {https://inrepo02.dkfz.de/record/277291},
}