ETS-1 Induces Endothelial-Like Differentiation and Promotes Metastasis in Non-Small Cell Lung Cancer

Abstract

Background/Aims: Recently, endothelial-like cells originating directly from tumor cells have been revealed. However, the mechanism remains unclear. ETS-1 (E26 transformation specific-1), a key transcription factor in the generation and maturation of ECs (endothelial cells), has been reported to be overexpressed in several cancers. Here, we reveal novel regulation of the endothelial-like differentiation of NSCLC (non-small cell lung cancer) cells by ETS-1. Methods: We up-regulated the expression of ETS-1 in NSCLC cell lines by H₂O₂ or lentiviral vector. Endothelial phenotypes, such as vWF (von Willebrand factor) and VE-cadherin were examined by Western blot analysis and immunofluorescence assay. Tube formation assay and phagocytotic activity assay were performed to evaluate ECs’ specific features on NSCLC cells. The effect of ETS-1 on metastasis was determined by wound healing assays, transwell assays and a xenograft tumor model. To explore the role of ETS-1 in the initiation and progression of NSCLC, we examined ETS-1 levels in NSCLC cancerous tissues and paired adjacent normal tissues by immunohistochemstry and analyzed the relationship between ETS-1 levels and clinicopathological parameters, as well as patient survival. Kaplan Meier plotter database was used to assess the prognostic value of ETS-1 in NSCLC. The association between ETS-1 levels and MVD (microvessel density) was analyzed to determine their role in angiogenesis. Results: With ETS-1 up-regulation, the expression of vWF and VE-cadherin was increased in NSCLC cells. Additionally, cells adopted several ECs’ specific features, including enhanced tube formation ability and uptake of Dil-ac-LDL (acetylated low-density lipoprotein) and lectin. ETS-1 up-regulation also promoted cell migration, invasion and adhesion. In addition, xenograft mice arising from ETS-1 over-expressing cells had more liver metastases. In the clinical specimens, ETS-1 expression was significantly higher in NSCLC cancerous tissues than adjacent nontumorous tissues and positively associated with tumor size, T stage, N stage and clinical stage. Patients with high levels of ETS-1 expression had significantly poorer OS (overall survival) and FP (first progression) than those with low expression. Furthermore, there was a positive correlation between ETS-1 level and MVD. Conclusion: Collectively, our data reveal that ETS-1 can induce the differentiation of tumor cells into endothelial-like cells and further promote metastatic dissemination in NSCLC.

Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells

“…High CD31 expression is often found in tumor tissues by immunohistochemistry and associated with a poor prognosis among cancer patients (Basilio-de-Oliveira and Pannain 2015 ; Cao et al 2018 ), but high CD31 secretion by tumor cells has rarely been analyzed by protein microarray or ELISA, as observed in this study. VE-cadherin, also known as cadherin-5, is an adhesion molecule uniquely expressed in endothelial cells that has been used to assess microvessels and angiogenesis in human breast cancer (Zhao et al 2018 ; Tang et al 2018 ; Zhou et al 2018 ). High expression of VE-cadherin in the tumor correlates with poor prognosis in human gastric cancer (Higuchi et al 2017 ), but the level of soluble VE-cadherin has not been detected in cancer cells or tissues.…”

MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling

“…The exogenous transfection of miR-532-3p remarkably promoted apoptosis and inhibited proliferation and invasion properties of CRC both in vivo and in vitro. The E26 oncogene homolog 1 (ETS1), a member of the ETS family of transcription factors (TFs) known to promote cellular growth and migration 12,13 , and transglutaminase 2 (TGM2), a well-known apoptosis attenuator, are both direct targets of miR-532-3p in CRC. In addition, TGM2 has been reported to be transcriptionally activated by ETS1 and inhibits apoptosis and associated with chemotherapy stress in CRC via the activation of Wnt/β-catenin signaling.…”

Identification of the Expression Signature and Potential Mechanisms of miR-493-3p in NSCLC using Bioinformatics Strategy: A Comprehensive Study from TCGA and GEO Datasets

“…Basis on the PPI network, nine hub genes (MKI67, MAD2L1, FEN1, SKA3, E2F1, SP1, ETS1, PHLPP2, TGFA) were identi ed. Since miR-493-3p is up-regulated in NSCLC, the target genes of miR-493-3p have greater potential lowexpressed in NSCLC, so we found ETS1 and PHLPP2 were lowly expressed in NSCLC patients compare with the normal tissues through GEPIA database, but EST1 was opposite to the previous studies for high expression in NSCLC tissues [41][42][43], PHLPP2 lowly expressed in NSCLC tissues and consistent with the previous studies [44,45] , and we also fund PHLPP2 lowly expressed in LUAD and LUSC tissues compare to normal lung tissues through Human Protein Atlas database. Moreover, Kaplan-Meier curve analysis indicated that NSCLC patients with high expression of PHLPP2 had a better OS.…”