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Nuclear respiratory factor 1 promotes spheroid survival and mesenchymal transition in mammary epithelial cells.
Oncogene ( IF 8 ) Pub Date : 2018-Jul-11 , DOI: 10.1038/s41388-018-0349-2
Yuanshuai Zhou , Zhongjuan Xu , Daniel Quan , Fan Zhang , Hai Zhang , Tongqian Xiao , Shulan Hou , Hong Qiao , Olivier Harismendy , Jean Y. J. Wang , Guangli Suo

Epithelial cells aggregate into spheroids when deprived of matrix, and the proclivity for spheroid formation and survival is a hallmark of normal and tumorigenic mammary stem cells. We show here that Nuclear Respiratory Factor 1 (NRF1) is a spheroid promoter by in silico identification of this transcription factor as highly connected to top shRNA-hits deduced from re-iterative selections for shRNAs enriched in MCF10A spheroids. NRF1-promoted spheroid survival is linked to its stimulation of mitochondrial OXPHOS, cell migration, invasion, and mesenchymal transition. Conversely, NRF1 knockdown in breast cancer MDA-MB-231 cells reduced spheroids, migration, invasion, and mesenchymal marker expression. NRF1 knockdown also reduced tumor burden in mammary fat pads and lungs of orthotopic- or tail vein-transplanted mice. With the Luminal A subtype of breast cancer, higher NRF1 expression is associated with lower survival. These results show that NRF1, an activator of mitochondrial metabolism, supports mammary spheroid survival and tumor development.

中文翻译:

核呼吸因子1促进乳腺上皮细胞中的球状细胞存活和间质转化。

当缺乏基质时,上皮细胞聚集成球状体,并且球状体形成和存活的倾向性是正常的和致瘤的乳腺干细胞的标志。我们在这里显示核呼吸因子1(NRF1)是球状启动子,通过计算机将该转录因子进行计算机鉴定,与从富含MCF10A球状体的shRNA的重复选择中推导的顶级shRNA命中高度相关。NRF1促进的球状细胞存活与其对线粒体OXPHOS的刺激,细胞迁移,侵袭和间充质转化有关。相反,乳腺癌MDA-MB-231细胞中的NRF1敲低减少了球体,迁移,侵袭和间充质标记物的表达。NRF1组合还可减少原位或尾静脉移植小鼠乳腺脂肪垫和肺部的肿瘤负担。对于Luminal A亚型的乳腺癌,较高的NRF1表达与较低的存活率相关。这些结果表明,线粒体代谢的激活剂NRF1支持乳腺球状体的存活和肿瘤的发展。
更新日期:2018-07-14
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