Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
Dev Cell. 2018 Jul 16;46(2):145-161.e10. doi: 10.1016/j.devcel.2018.06.012.
Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.
Nrf2 是抗氧化防御系统的关键调节因子，药理学激活 Nrf2 是预防癌症和促进组织修复的有前途的策略。然而，我们在这里表明，成纤维细胞中 Nrf2 的激活会诱导细胞衰老。我们使用转录组学、基质蛋白质组学、染色质免疫沉淀和生物信息学的组合，证明激活 Nrf2 的成纤维细胞沉积促进衰老的基质，纤溶酶原激活物抑制剂-1 是衰老程序的关键诱导剂。在体内，成纤维细胞中 Nrf2 的激活促进了皮肤伤口的再上皮化，但也促进了皮肤肿瘤的发生。这种促肿瘤活性具有普遍的相关性，因为皮肤成纤维细胞中 Nrf2 的激活诱导了来自不同小鼠和人类肿瘤的癌症相关成纤维细胞特征基因的表达。因此，激活的 Nrf2 可作为癌症相关成纤维细胞表型的标志物。这些数据突出了 Nrf2 的光明面和黑暗面，以及对这种转录因子进行时间控制激活的必要性。
