ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase

Abstract

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.

<p>MicroRNA-769-5p Inhibits Pancreatic Ductal Adenocarcinoma Progression by Directly Targeting and Downregulating ETS Proto-Oncogene 1</p>

“…ETS1 belongs to the ETS family of transcription factors that share a unique DNA binding domain. 19 It is a 54 kDa nuclear protein and implicated in the tumorigenesis and tumor development. 20 ETS1 results a great deal of tumor behavior, including rell proliferation, cell cycle, apoptosis, angiogenesis, migration, invasion and epithelial-mesenchymal transition.…”

Knockdown of linc00152 inhibits the progression of gastric cancer by regulating microRNA-193b-3p/ETS1 axis

“…41 The knockdown of ETS1 inhibited cell proliferation, migration and invasion in ovarian cancer. 42 Also, prior studies manifested that ETS1 expression was notably upregulated in GC tissues and cells . 22,43 and associated with aggressive tumor behaviors and poor prognosis in GC.…”

Integrated analysis of DNA methylation and mRNA expression profiles to identify key genes in head and neck squamous cell carcinoma

“…ETS1, an essential member of the ETS transcription factors, participated in a variety of crucial biological processes underlying tumor progression, such as cell invasion, epithelial-mesenchymal transition, angiogenesis, and drug resistance [37]. Furthermore, the cross-talk of ETS1 with microenvironment makes it an essential factor for tumor metastasis, serving as a candidate therapeutic target [38]. PIK3CD, whose ectopic expression could affect the biological phenotypes of multiple cancers, was reported to regulate the PI3K signaling pathway [39].…”