title: Activation of Akt at T308 and S473 in alcohol, tobacco and HPV-induced HNSCC: is there evidence to support a prognostic or diagnostic role?
abstract: BACKGROUND
  Tobacco, alcohol and HPV infection are associated with increased risk of HNSCC. However, little is known about the underlying signaling events influencing risk. We aimed to investigate the relationship between these risk factors and Akt phosphorylation, to determine prognostic value.
  
  
  METHODS
  VEGF-positive HNSCC biopsies, with known HPV status, were analyzed by immunohistochemistry (IHC) for Akt, phosphorylated at residues S473 and T308. Comparisons between the tissues were carried out using a Mann-Whitney U test. Associations between the variables and continuous immunohistochemical parameters were evaluated with general linear models. Patient characteristics and pAkt IHC score were analyzed for possible association with overall survival by Cox proportional hazard models.
  
  
  RESULTS
  Immunohistochemistry revealed that cancer patients had significantly higher levels of pAkt T308 than S473 (P < 0.001). Smoking and alcohol were found to be independent risk factors for Akt phosphorylation at T308 (P = 0.022 and 0.027, respectively). Patients with tumors positive for HPV or pAkt S473 had a poorer prognosis (P = 0.005, and 0.004, respectively). Patients who were heavy drinkers were 49 times more likely to die than non-drinkers (P = 0.003). Patients with low pAkt T308 were more likely to be HPV positive (P = 0.028). Non-drinkers were also found to have lower levels of pAkt T308 and were more likely to have tumors positive for HPV than heavy drinkers (P = 0.044 and 0.007, respectively).
  
  
  CONCLUSIONS
  This study suggests different mechanisms of carcinogenesis are initiated by smoking, alcohol and HPV. Our data propose higher phosphorylation of Akt at T308 as a reliable biomarker for smoking and alcohol induced HNSCC progression and higher phosphorylation of Akt at S473 as a prognostic factor for HNSCC.
authors.affiliation: Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Islam
authors.affiliation: Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Ellis
authors.affiliation: Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK.
authors.forename: Michaelina
authors.initials: M
authors.lastname: Macluskey
authors.affiliation: Division of Population Health Science, Medical Research Institute, University of Dundee, Dundee, DD2 4BF UK.
authors.forename: Lynda
authors.initials: L
authors.lastname: Cochrane
authors.affiliation: Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jones
keywords: Biomarker; HNSCC; Prognosis; Risk factors; pAkt S473; pAkt T308