Centro de Investigaciones Inmunológicas Básicas y Aplicadas, CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina.
Laboratorio de Expresión Génica en Mama y Apoptosis, LEGMA, IFIBYNE-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
J Mammary Gland Biol Neoplasia. 2020 Jun;25(2):163-172. doi: 10.1007/s10911-020-09448-1. Epub 2020 Apr 4.
It has been established that ZFP36 (also known as Tristetraprolin or TTP) promotes mRNA degradation of proteins involved in inflammation, proliferation and tumor invasiveness. In mammary epithelial cells ZFP36 expression is induced by STAT5 activation during lactogenesis, while in breast cancer ZFP36 expression is associated with lower grade and better prognosis. Here, we show that the AP-1 transcription factor components, i.e. JUN, JUNB, FOS, FOSB, in addition to DUSP1, EGR1, NR4A1, IER2 and BTG2, behave as a conserved co-regulated group of genes whose expression is associated to ZFP36 in cancer cells. In fact, a significant down-modulation of this gene network is observed in breast, liver, lung, kidney, and thyroid carcinomas compared to their normal counterparts. In breast cancer, the normal-like and Luminal A, show the highest expression of the ZFP36 gene network among the other intrinsic subtypes and patients with low expression of these genes display poor prognosis. It is also proposed that AP-1 regulates ZFP36 expression through responsive elements detected in the promoter region of this gene. Culture assays show that AP-1 activity induces ZFP36 expression in mammary cells in response to prolactin (PRL) treatment thorough ERK1/2 activation. These results suggest that JUN, JUNB, FOS and FOSB are not only co-expressed, but would also play a relevant role in regulating ZFP36 expression in mammary epithelial cells.
已经确定 ZFP36（也称为 Tristetraprolin 或 TTP）可促进涉及炎症、增殖和肿瘤侵袭的蛋白质的 mRNA 降解。在乳腺上皮细胞中，ZFP36 的表达在泌乳期由 STAT5 激活诱导，而在乳腺癌中，ZFP36 的表达与较低的分级和较好的预后相关。在这里，我们表明 AP-1 转录因子成分，即 JUN、JUNB、FOS、FOSB，除了 DUSP1、EGR1、NR4A1、IER2 和 BTG2 之外，还表现为一个保守的共同调节基因群，其表达与癌细胞中的 ZFP36 相关。事实上，与正常组织相比，乳腺癌、肝癌、肺癌、肾癌和甲状腺癌中观察到该基因网络的显著下调。在乳腺癌中，正常样和 Luminal A 显示出 ZFP36 基因网络在其他内在亚型中的最高表达，而这些基因表达水平低的患者预后不良。还提出 AP-1 通过该基因启动子区域中检测到的响应元件来调节 ZFP36 的表达。培养实验表明，AP-1 活性通过 ERK1/2 激活诱导泌乳期乳腺细胞中 ZFP36 的表达。这些结果表明，JUN、JUNB、FOS 和 FOSB 不仅共表达，而且在调节乳腺上皮细胞中 ZFP36 的表达方面也发挥着重要作用。
