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

28 Pages Posted: 6 Sep 2019

See all articles by Haoran Feng

Haoran Feng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Kun Liu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Xiaopin Ji

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Yi Peng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

You Li

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Tao Zhang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Changgang Wang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Yimei Jiang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Yiqing Shi

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Zhijian Jin

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Xianze Chen

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Weihua Qiu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Xi Cheng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Ren Zhao

Shanghai Jiao Tong University (SJTU) - Department of General Surgery; Shanghai Jiao Tong University (SJTU), School of Medicine, Ruijin Hospital, Department of Surgery, Shanghai Institute of Digestive Surgery

More...

Abstract

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.

Keywords: ETV5, Colorectal cancer, Bevacizumab resistance, Angiogenesis, VEGFA, VEGF signals pathway

Suggested Citation

Feng, Haoran and Liu, Kun and Ji, Xiaopin and Peng, Yi and Li, You and Zhang, Tao and Wang, Changgang and Jiang, Yimei and Shi, Yiqing and Jin, Zhijian and Chen, Xianze and Qiu, Weihua and Cheng, Xi and Zhao, Ren, ETV5 Promotes Angiogenesis and Accelerates Bevacizumab Resistance in Colorectal Cancer by Transcriptionally Activating VEGFA (August 29, 2019). Available at SSRN: https://ssrn.com/abstract=3445530

Haoran Feng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Kun Liu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Xiaopin Ji

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Yi Peng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

You Li

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Tao Zhang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

Changgang Wang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Yimei Jiang

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Yiqing Shi

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Zhijian Jin

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Xianze Chen

Shanghai Jiao Tong University (SJTU) - Department of General Surgery

Shanghai
China

Weihua Qiu

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

Xi Cheng

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

Ren Zhao (Contact Author)

Shanghai Jiao Tong University (SJTU) - Department of General Surgery ( email )

Shanghai
China

Shanghai Jiao Tong University (SJTU), School of Medicine, Ruijin Hospital, Department of Surgery, Shanghai Institute of Digestive Surgery ( email )

Shanghai, 200025
China

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