Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network
Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network
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DOI：
10.1016/j.cell.2008.03.039
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发表时间：
2008-06-13
期刊：
影响因子：
64.5
通讯作者：
Peeper, Daniel S.
中科院分区：
文献类型：
--
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
致癌基因诱导的细胞衰老（OIS）是对致癌事件的有效癌症保护反应，从而消除了从增殖性池的早期肿瘤细胞。使用遗传和生物信息学分析，我们发现OIS专门与炎症转录组的激活有关。诱导的基因包括多效性细胞因子白细胞介素6（IL-6），该基因在衰老细胞的分泌后以旁分泌方式作用。出乎意料的是，执行OI也需要IL-6，但处于细胞自主模式。它的耗尽导致炎症网络崩溃并废除了衰老的进入和维护。此外，我们证明了转录因子C/EBPβ与IL-6合作，以扩大包括IL-8在内的炎症网络的激活。在人类结肠腺瘤中，IL-8与被捕的P16（Ink4a） - 阳性上皮特异性共定位。我们提出了一个模型，其中特定白细胞介素的上下文依赖性细胞抑制和诺言作用有助于将衰老与炎症表型和癌症联系起来。
Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBP beta cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16(INK4A)-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer.