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USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis
  1. Lionel Costa1,2,3,
  2. Sébastien Corre4,
  3. Valérie Michel1,
  4. Krysten Le Luel1,3,
  5. Julien Fernandes1,5,
  6. Jason Ziveri1,6,
  7. Gregory Jouvion7,
  8. Anne Danckaert5,
  9. Nicolas Mouchet4,
  10. David Da Silva Barreira1,8,
  11. Javier Torres9,
  12. Margarita Camorlinga9,
  13. Mario Milco D'Elios10,
  14. Laurence Fiette7,11,
  15. Hilde De Reuse1,
  16. Marie-Dominique Galibert4,12,
  17. Eliette Touati1
  1. 1Unit of Helicobacter Pathogenesis, Department of Microbiology, CNRS ERL6002, Institut Pasteur, Paris, France
  2. 2INSERM U1016, CNRS UMR 8104, Institut Cochin, Paris, France
  3. 3Université Paris Diderot, Sorbone Paris Cité, Paris, France
  4. 4Institut de Génétique et Développement, Université de Rennes 1, Rennes, France
  5. 5UtechS PBI-C2RT, Institut Pasteur, Paris, France
  6. 6Pathogenesis of Systemic Infection, Institut Fédératif de Recherche Necker-Enfants Malades, Paris, France
  7. 7Unit of Experimental Neuropathology, Department of Global Health, Institut Pasteur, Paris, France
  8. 8AgroSup, Laboratoire PAM UMR A 02.102, Université de Bourgogne, Dijon, France
  9. 9Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Pediatria, Instituto Mexicano del Seguro Social (IMSS), México city, Mexico
  10. 10Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
  11. 11Institut Mutualiste Montsouris, Paris, France
  12. 12CHU, Department of Molecular Genetics and Genomics, Université de Rennes 1, Rennes, France
  1. Correspondence to Dr Eliette Touati, Unit of Helicobacter Pathogenesis, Department of Microbiology, Institut Pasteur, Paris 75015, France; etouati{at}


Objective Helicobacter pylori (Hp) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp-mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis.

Design Human gastric epithelial cell lines were infected with Hp7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1, p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1-/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance.

Results In vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp-induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects.

Conclusion Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.

  • helicobacter pylori infection
  • oncogenes
  • DNA damage
  • genetic instability
  • gastric cancer
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  • M-DG and ET are joint senior authors.

  • Contributors Study concept and design: LC, SC, M-DG, ET; experiments and acquisition of data: LC, SC, VM, KLL, JF, JZ, GJ, NM, DDSB, LF, ET; analysis of data and statistics: LC, SC, AD, M-DG, ET; patient data and samples collection: JT, MC, MMD; drafting of the manuscript: SC, M-DG, ET; critical revision of the manuscript: JT, MMD, HDR; reading and approval of the manuscript: all authors; study supervision and funding: MD-G, ET.

  • Funding This work was supported by funding from the Odyssey Reinsurance Company to ET, the West committee of the Ligue Nationale Contre le Cancer (LNCC) and the UMS Biosit to MDG. JT received financial support from Fondo de Investigacion en Salud, IMSS, Mexico (FIS/IMSS/PROT/PRIO/13/027). The LNCC provided a doctoral fellowship to LC and the Odyssey Reinsurance company financed JF postdoctoral fellowship. KLL is a doctoral fellow from the University Paris Diderot, Ecole Doctorale Bio Sorbonne Paris Cité (BioSPC).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Local Ethical Committees from the National Council for Research on Health, Instituto Mexicano del Seguro Social, Mexico and Florence University Hospital, Italy. The project was approved by the Comité d’Ethique en Expérimentation Animale (CETEA), Institut Pasteur (Ref 00317.02) and the Federative Structure of Research, Rennes (Ref APAFIS#905–2015060515515795 v4).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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