title: Photon-induced cell migration and integrin expression promoted by DNA integration of HPV16 genome.
abstract: BACKGROUND
  Persistent human papilloma virus 16 (HPV16) infections are a major cause of cervical cancer. The integration of the viral DNA into the host genome causes E2 gene disruption which prevents apoptosis and increases host cell motility. In cervical cancer patients, survival is limited by local infiltration and systemic dissemination. Surgical control rates are poor in cases of parametrial infiltration. In these patients, radiotherapy (RT) is administered to enhance local control. However, photon irradiation itself has been reported to increase cell motility. In cases of E2-disrupted cervical cancers, this phenomon would impose an additional risk of enhanced tumor cell motility. Here, we analyze mechanisms underlying photon-increased migration in keratinocytes with differential E2 gene status.
  
  
  METHODS
  Isogenic W12 (intact E2 gene status) and S12 (disrupted E2 gene status) keratinocytes were analyzed in fibronectin-based and serum-stimulated migration experiments following single photon doses of 0, 2, and 10 Gy. Quantitative FACS analyses of integrin expression were performed.
  
  
  RESULTS
  Migration and adhesion are increased in E2 gene-disrupted keratinocytes. E2 gene disruption promotes attractability by serum components, therefore, effectuating the risk of local infiltration and systemic dissemination. In S12 cells, migration is further increased by photon RT which leads to enhanced expression of fibronectin receptor integrins.
  
  
  CONCLUSIONS
  HPV16-associated E2 gene disruption is a main predictor of treatment-refractory cancer virulence. E2 gene disruption promotes cell motility. Following photon RT, E2-disrupted tumors bear the risk of integrin-related infiltration and dissemination.
authors.affiliation: Department of Radiation Therapy and Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany, Stefan.rieken@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rieken
authors.forename: Florian
authors.initials: F
authors.lastname: Simon
authors.forename: Daniel
authors.initials: D
authors.lastname: Habermehl
authors.forename: Jan Oliver
authors.initials: JO
authors.lastname: Dittmar
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.forename: Klaus
authors.initials: K
authors.lastname: Weber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Katja
authors.initials: K
authors.lastname: Lindel
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000502:physiology* / Q000528:radiation effects; D004279:DNA, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D016679:Genome, Viral / Q000235:genetics*; D052162:Human papillomavirus 16 / Q000235:genetics*; D016023:Integrins / Q000378:metabolism*; D015603:Keratinocytes / Q000502:physiology* / Q000528:radiation effects; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D017785:Photons; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000528:radiation effects; D011829:Radiation Dosage; D014162:Transfection / Q000379:methods; D016662:Virus Integration / Q000235:genetics
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D016023:Integrins; D009856:Oncogene Proteins, Viral