Please use this identifier to cite or link to this item: http://buratest.brunel.ac.uk/handle/2438/9212
Title: Identification of a gene signature of a pre-transformation process by senescence evasion in normal human epidermal keratinocytes
Authors: Martin, N
Salazar-Cardozo, C
Vercamer, C
Ott, L
Marot, G
Slijepcevic, P
Abbadie, C
Pluquet, O
Keywords: AKR1Cs;Gene expression profile;Keratinocytes;Neoplastic transformation;Senescence;Xenobiotics
Issue Date: 2014
Publisher: BioMed Central Ltd.
Citation: Molecular Cancer, 2014, 13 (1): 151, June 2014
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. © 2014 Martin et al.; licensee BioMed Central Ltd.
Description: Copyright @ 2014 Martin et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
URI: http://www.molecular-cancer.com/content/13/1/151
http://bura.brunel.ac.uk/handle/2438/9212
DOI: http://dx.doi.org/10.1186/1476-4598-13-151
ISSN: 1476-4598
Appears in Collections:Biological Sciences
Dept of Life Sciences Research Papers

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