ETS1型
肿瘤微环境
旁分泌信号
癌症研究
生物
下调和上调
转移
转录因子
细胞生物学
运行x1
焦点粘着
信号转导
癌症
遗传学
基因
受体
肿瘤细胞
作者
Sunil Tomar,Joshua P. Plotnik,James A. Haley,Joshua Scantland,Subramanyam Dasari,Zahir Sheikh,Robert E. Emerson,Dean Lenz,Peter C. Hollenhorst,Anirban K. Mitra
标识
DOI:10.1016/j.canlet.2017.11.012
摘要
Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK.
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