ETV5 Promotes Angiogenesis and Accelerates Bevacizumab Resistance in Colorectal Cancer by Transcriptionally Activating VEGFA

E26 transformation-specific variant 5 (ETV5) has been recently implicated in the progression and metastasis of numbers of cancers. In our previous study, our data revealed that ETV5 promotes CRC proliferation and angiogenesis. However, the specific mechanism of action of ETV5 in the vascular endothelium and its effects on antiangiogenic drugs still need further characterization. In this study, ETV5 was shown to regulate angiogenesis by inducing the transcription of vascular endothelial growth factor A (VEGFA) in vitro and in vivo. Furthermore, overexpression of ETV5 in CRC cells lead to increased secretion of VEGFA that acted on vascular endothelial cells, thereby causing activation of AKT, ERK and p38 in endothelial cells. Moreover, an increase in ETV5 enhanced bevacizumab resistance in CRC, and inhibition of VEGFA decreased angiogenesis and bevacizumab resistance in ETV5-overexpressing CRC cells. Moreover, our study showed that CRC patients with both ETV5 and VEGFA upregulation tended to have the worst prognosis. In summary, we confirmed that ETV5 could enhance CRC angiogenesis and proliferation by targeting VEGFA and could accelerate bevacizumab resistance through AKT, ERK and p38 in endothelial cells. These findings validate our previous results. In addition, our novel results represent a potentially new therapeutic strategy and biomarker for antiangiogenic therapy against CRC. Funding: This study received funding from the National Natural Science Foundation of China (81772558 to Weihua Qiu), Shanghai Hospital Development Center (16CR2064B to Ren Zhao), Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine (2018zy09 to Kun Liu) and Shanghai Municipal Commission of Health and Family Planning (201540026 to Ren Zhao). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: All the experiments involving in human specimens and animals were in accordance with the ethical code and recommendation issued by Ethics Committee of Human Experimentation and Chinese Animal Community and with the Helsinki Declaration of 1975, as revised in 2008.