Laboratory of "Stress and Cancer", Inserm U830, Institut Curie, 75248 Paris Cedex 05, France.
EMBO Mol Med. 2010 Jun;2(6):211-30. doi: 10.1002/emmm.201000073.
JunD regulates genes involved in antioxidant defence. We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour development. In a model of mammary carcinogenesis, junD inactivation increased tumour incidence and revealed an associated reactive stroma. junD-inactivation in the stroma was sufficient to shorten tumour-free survival rate and enhance metastatic spread. ROS promoted conversion of fibroblasts into highly migrating myofibroblasts through accumulation of the hypoxia-inducible factor (HIF)-1alpha transcription factor and the CXCL12 chemokine. Accordingly, treatment with an antioxidant reduced the levels of HIF and CXCL12 and numerous myofibroblast features. CXCL12 accumulated in the stroma of HER2-human breast adenocarcinomas. Moreover, HER2 tumours exhibited a high proportion of myofibroblasts, which was significantly correlated to nodal metastases. Interestingly, this subset of tumours exhibited a significant nuclear exclusion of JunD and revealed an associated oxido-reduction signature, further demonstrating the relevance of our findings in human cancers. Collectively, our data uncover a new mechanism by which oxidative stress increases the migratory properties of stromal fibroblasts, which in turn potentiate tumour dissemination.
JunD 调控参与抗氧化防御的基因。我们利用 junD 缺失导致的慢性氧化应激，研究活性氧（ROS）在肿瘤发展中的作用。在乳腺致癌模型中，junD 失活增加了肿瘤的发生率，并揭示了与之相关的反应性基质。基质中 junD 的失活足以缩短无肿瘤生存率并增强转移扩散。ROS 通过积累缺氧诱导因子（HIF）-1α转录因子和趋化因子 CXCL12，促进成纤维细胞转化为高迁移性肌成纤维细胞。因此，抗氧化剂治疗可降低 HIF 和 CXCL12 的水平以及许多肌成纤维细胞特征。CXCL12 在 HER2 人乳腺腺癌的基质中积累。此外，HER2 肿瘤表现出大量的肌成纤维细胞，这与淋巴结转移有显著相关性。有趣的是，这组肿瘤表现出 JunD 的显著核排斥，并揭示了相关的氧化还原特征，进一步证明了我们在人类癌症中的发现的相关性。总之，我们的数据揭示了一种新的机制，即氧化应激如何增加基质成纤维细胞的迁移特性，进而增强肿瘤的扩散。
