title: Activation of the mammalian target of rapamycin signalling pathway in epidermal tumours and its correlation with cyclin-dependent kinase 2.
abstract: BACKGROUND
  The enzyme mammalian target of rapamycin (mTOR) integrates many different cellular signals to control cell growth and proliferation, protein synthesis and breakdown, and other processes. Dysregulation of mTOR is implicated in a range of human diseases, including cancers and cardiovascular disorders. To date, there has been no report on the expression of protein kinase B (AKT)/mTOR cell signalling in epidermal tumours.
  
  
  OBJECTIVE
  This study was designed to investigate the activation of the mTOR signalling pathway in epidermal tumours and to correlate this with cyclin-dependent kinase 2 (CDK2) expression.
  
  
  METHODS
  Immunohistological staining was performed with phosphorylated (p-) AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-ribosomal protein S6 (p-S6), p-p70 ribosomal protein S6 kinase 1 (p-p70S6K1) and CDK2 in 15 cases each of seborrhoeic keratosis, actinic keratosis, keratoacanthoma and Bowen's disease (BD), and 25 cases of squamous cell carcinoma (SCC). Fifteen normal skin (NS) samples served as control.
  
  
  RESULTS
  Among 85 tumours, 40 (47%) were positive for p-AKT, 31 (36%) for p-mTOR, 44 (52%) for p-4EBP1, 38 (45%) for p-S6, and 39 (46%) for p-p70S6K1. CDK2 immunostaining was positive in all cases of SCC and BD, and in 67% of benign tumours. All of these markers were stained much more frequently in malignant tumours than in benign tumours or NS. p-AKT, p-mTOR, p-4EBP1, p-p70S6K1 and p-S6 each showed high correlation with CDK2.
  
  
  CONCLUSIONS
  Constitutive activation of the AKT/mTOR pathway was frequent in epidermal tumours, especially in malignant tumours. Activation was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in epidermal tumours.
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Nakahara
authors.forename: M
authors.initials: M
authors.lastname: Takahara
authors.forename: M
authors.initials: M
authors.lastname: Kido
authors.forename: L
authors.initials: L
authors.lastname: Dugu
authors.forename: H
authors.initials: H
authors.lastname: Uchi
authors.forename: S
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Y-T
authors.initials: YT
authors.lastname: Tu
authors.forename: Y
authors.initials: Y
authors.lastname: Moroi
authors.forename: M
authors.initials: M
authors.lastname: Furue
mesh_terms: D001913:Bowen's Disease / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D055623:Keratosis, Actinic / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D020123:Sirolimus