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@ARTICLE{Hoffmann:298212,
      author       = {M. Hoffmann and S. Hille and A. Fazel and M. Laudien and S.
                      Wiegand and M. Müller$^*$ and O. J. Müller and E. S.
                      Quabius},
      title        = {{M}echanistic insights into {HPV}-positivity in non-smokers
                      and {HPV}-negativity in smokers with head and neck cancer.},
      journal      = {Frontiers in oncology},
      volume       = {14},
      issn         = {2234-943X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2025-00219},
      pages        = {1484319},
      year         = {2025},
      abstract     = {Several aspects of the involvement of HPV in the
                      pathogenesis of HPV-associated diseases remain poorly
                      understood including mechanistic aspects of infection and
                      the question of why the majority of HPV-positive
                      HNSCC-patients are non-smokers, whereas HPV-negatives are
                      smokers. Our previous research, based on 1,100 patient
                      samples, hypothesized an explanation for this phenomenon:
                      Smoking induces upregulation of a mucosal protective protein
                      (SLPI), which competes with HPV for binding to Annexin A2
                      (AnxA2), pivotal for HPV cell entry. Here we investigate the
                      mechanistic aspects of our hypothesis using transfection
                      assays.HaCaT and HeLa cell lines were used to investigate
                      the effects of shRNA transfection and nicotine exposure on
                      HPV16-PsV-uptake. Cells were treated with Lipofectamine™
                      RNAiMAX for 48 or 72 hours with specific
                      shRNA-concentrations, while nicotine was added to the cell
                      medium at the indicated concentrations. Protein isolation,
                      SLPI- and AnxA2-quantification, LDH cytotoxicity assessment,
                      HPV16-PsV-uptake measurement, mRNA-isolation, cDNA-synthesis
                      and RT-qPCR were performed.In vitro transfection experiments
                      with HPV16 pseudovirions (PsVs) showed that PsVs entered
                      cells significantly better when SLPI was downregulated and
                      significantly less when AnxA2 was downregulated. Nicotine
                      exposure increased SLPI levels and reduced PsV uptake.The
                      overexpression of SLPI caused by tobacco-smoking can hinder
                      HPV cell entry by binding to AnxA2 and thus prevent
                      successful HPV infection. Conversely, non-smokers have lower
                      SLPI-levels, associated with an excess of unbound AnxA2,
                      favoring HPV cell-entry. These findings support our
                      hypothesis, suggesting a paradigm shift in understanding
                      virus-related pathogenesis, particularly in the head and
                      neck region, and the nature of HPV infection.},
      keywords     = {Annexin A2 (Other) / HNSCC (Other) / HPV (Other) / SLPI
                      (Other) / smoking (Other) / viral cell entry (Other) / virus
                      infection (Other)},
      cin          = {D335},
      ddc          = {610},
      cid          = {I:(DE-He78)D335-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39850816},
      pmc          = {pmc:PMC11754403},
      doi          = {10.3389/fonc.2024.1484319},
      url          = {https://inrepo02.dkfz.de/record/298212},
}