Martin Nathalie, Salazar-Cardozo Clara, Vercamer Chantal, Ott Louise, Marot Guillemette, Slijepcevic Predrag, Abbadie Corinne, Pluquet Olivier
CNRS, UMR8161, Institut de Biologie de Lille, 1 rue Calmette, 59000 Lille, France.
Mol Cancer. 2014 Jun 14;13:151. doi: 10.1186/1476-4598-13-151.
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.
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.
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.
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.
流行病学数据表明，人类癌症的发病率高度依赖于年龄。然而，与年龄相关的分子致癌过程中，细胞向肿瘤状态转变的初始步骤仍知之甚少，这主要是由于缺乏强大的模型。在先前的一项研究中，我们发现正常人表皮角质形成细胞（NHEK）会自发且系统性地逃离衰老状态，从而产生癌前新兴细胞。
在此，该模型被用于分析与年龄相关的细胞转化早期步骤相关的基因表达谱。我们将生长中的或衰老的NHEK与衰老后出现的新兴细胞的基因表达谱进行了比较。使用limma软件包的线性建模功能进行数据分析，基于适度统计量得出双侧t检验或F检验。根据Benjamini Hochberg方法控制错误发现率，对p值进行多重检验校正。这两次比较中差异基因表达谱产生的共同基因集揭示了一个由286个基因组成的衰老后肿瘤发生（PSNE）基因特征。
这些基因中约有一半已被报道与癌症或癌前皮肤疾病有关。然而，生物信息学分析并未在该特征中突出典型的癌症通路，而是突出了代谢通路，其中首当其冲的是细胞色素P450对外源生物的代谢。为了验证该特征作为通过逃避衰老实现转化前特征的相关性，我们使细胞色素P450对外源生物代谢的两个成分AKR1C2和AKR1C3失活。在衰老平台期开始时进行这种失活操作，并不会改变衰老状态本身，但会显著降低PSNE的频率。相反，AKR1C2的过表达而非AKR1C3的过表达会增加PSNE的频率。
据我们所知，本研究首次确定正常角质形成细胞中代谢通路的重编程是从衰老转变为转化前状态的潜在决定因素。
