title: Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma.
abstract: BACKGROUND
  The purpose of this study was to examine the hypoxic regulation of the PKR-like endoplasmic reticulum kinase (PERK)/activating transcription factor-4 (ATF4)/lysosome-associated membrane protein 3 (LAMP3)-arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines.
  
  
  RESULTS
  In patients with HNSCC, high LAMP3 expression correlated with N classification (p = .019) and the occurrence of distant metastases during follow-up (p = .039). Patients with high LAMP3 levels had a worse metastasis-free survival (p = .008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p-PERK, p-eIF2α, ATF4, and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to endoplasmic reticulum-stress stimulated PERK, ATF4, and LAMP3 expression.
  
  
  CONCLUSIONS
  LAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3-arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anika
authors.initials: A
authors.lastname: Nagelkerke
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Stegeman
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery and Department of Medical Biochemistry, Turku University Hospital and University of Turku, Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D015996:Survival Rate; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D059666:Lysosomal-Associated Membrane Protein 3
chemical_list: D051701:Activating Transcription Factor 4; D051907:Lysosomal Membrane Proteins; D009363:Neoplasm Proteins; D019892:eIF-2 Kinase; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3
keywords: endoplasmic reticulum stress; head and neck squamous cell carcinoma (HNSCC); hypoxia; lysosome-associated membrane protein 3 (LAMP3); unfolded protein response (UPR)