title: Identification of a gene signature of a pre-transformation process by senescence evasion in normal human epidermal keratinocytes.
abstract: BACKGROUND
  Epidemiological data show that the incidence of carcinomas in humans is highly dependent on age. However, the initial steps of the age-related molecular oncogenic processes by which the switch towards the neoplastic state occurs remain poorly understood, mostly due to the absence of powerful models. In a previous study, we showed that normal human epidermal keratinocytes (NHEKs) spontaneously and systematically escape from senescence to give rise to pre-neoplastic emerging cells.
  
  
  METHODS
  Here, this model was used to analyze the gene expression profile associated with the early steps of age-related cell transformation. We compared the gene expression profiles of growing or senescent NHEKs to post-senescent emerging cells. Data analyses were performed by using the linear modeling features of the limma package, resulting in a two-sided t test or F-test based on moderated statistics. The p-values were adjusted for multiple testing by controlling the false discovery rate according to Benjamini Hochberg method.The common gene set resulting of differential gene expression profiles from these two comparisons revealed a post-senescence neoplastic emergence (PSNE) gene signature of 286 genes.
  
  
  RESULTS
  About half of these genes were already reported as involved in cancer or premalignant skin diseases. However, bioinformatics analyses did not highlight inside this signature canonical cancer pathways but metabolic pathways, including in first line the metabolism of xenobiotics by cytochrome P450. In order to validate the relevance of this signature as a signature of pretransformation by senescence evasion, we invalidated two components of the metabolism of xenobiotics by cytochrome P450, AKR1C2 and AKR1C3. When performed at the beginning of the senescence plateau, this invalidation did not alter the senescent state itself but significantly decreased the frequency of PSNE. Conversely, overexpression of AKR1C2 but not AKR1C3 increased the frequency of PSNE.
  
  
  CONCLUSIONS
  To our knowledge, this study is the first to identify reprogrammation of metabolic pathways in normal keratinocytes as a potential determinant of the switch from senescence to pre-transformation.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Martin
authors.forename: Clara
authors.initials: C
authors.lastname: Salazar-Cardozo
authors.forename: Chantal
authors.initials: C
authors.lastname: Vercamer
authors.forename: Louise
authors.initials: L
authors.lastname: Ott
authors.forename: Guillemette
authors.initials: G
authors.lastname: Marot
authors.forename: Predrag
authors.initials: P
authors.lastname: Slijepcevic
authors.forename: Corinne
authors.initials: C
authors.lastname: Abbadie
authors.affiliation: CNRS, UMR8161, Institut de Biologie de Lille, 1 rue Calmette, 59000 Lille, France. olivier.pluquet@ibl.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pluquet
mesh_terms: D000375:Aging / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000235:genetics; D004817:Epidermis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D059467:Transcriptome