Identification of a gene signature of a pre-transformation process by senescence evasion in normal human epidermal keratinocytes

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• 作者：Nathalie Martin (1) (2) (3) (4)
  Clara Salazar-Cardozo (1) (2) (3) (4)
  Chantal Vercamer (1) (2) (3) (4)
  Louise Ott (3) (8)
  Guillemette Marot (5) (6)
  Predrag Slijepcevic (7)
  Corinne Abbadie (1) (2) (3) (4)
  Olivier Pluquet (1) (2) (3) (4)
  
  1. CNRS ; UMR8161 ; Institut de Biologie de Lille ; 1 rue Calmette ; 59000 ; Lille ; France
  2. Universit茅 Lille 1 Sciences et Techniques ; 59650 ; Villeneuve d鈥橝scq ; France
  3. Universit茅 Lille 2 Droit et Sant茅 ; 59000 ; Lille ; France
  4. Institut Pasteur de Lille ; 59000 ; Lille ; France
  8. INSERM UMR_S 1109 ; Centre de Recherche d鈥橧mmunologie et d鈥橦茅matologie ; F茅d茅ration de M茅decine Translationnelle de Strasbourg (FMTS) ; Universit茅 de Strasbourg ; Strasbourg Cedex ; France
  5. Inria Lille-Nord Europe MODAL ; 40 avenue Halley ; 59650 ; Villeneuve d鈥橝scq ; France
  6. EA2694 Universit茅 Lille 2 Droit et Sant茅 ; 59000 ; Lille ; France
  7. Brunel Institute of Cancer Genetics and Pharmacogenomics ; Brunel University ; Uxbridge ; UK
  
• 关键词：Senescence ; Neoplastic transformation ; Xenobiotics ; AKR1Cs ; Keratinocytes ; Gene expression profile
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：1,367 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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.