State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
State Key Laboratory of Natural Medicines, Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China.
Nat Commun. 2019 Jul 19;10(1):3210. doi: 10.1038/s41467-019-11278-7.
Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.
越来越多的证据表明，锌指转录因子 ZEB1 在几种肿瘤的基质中表达为主。然而，基质中 ZEB1 在肿瘤进展中的作用仍未被探索。在这项研究中，当我们在人类数据库中进行查询时，我们发现表达高水平 ZEB1 的乳腺癌患者的无复发生存率显著降低。我们使用乳腺癌的小鼠模型表明，基质成纤维细胞中 ZEB1 的失活抑制了肿瘤的起始、进展和转移。我们将其与减少细胞外基质重塑、免疫细胞浸润和降低血管生成相关联。基质成纤维细胞中 ZEB1 的缺失增加了 p53 对 FGF2/7、VEGF 和 IL6 启动子的乙酰化、表达和募集，从而减少它们在周围基质中的产生和分泌。重要的是，在 ZEB1 基质缺失的乳腺肿瘤中 p53 的缺失足以恢复受损的癌症生长和进展。我们的研究结果确定了 ZEB1/p53 轴作为一种促进乳腺上皮肿瘤的基质特异性信号通路。
