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LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer

Oncogene volume 37, pages 4094–4109 (2018)Cite this article

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Abstract

Angiogenesis can aggravate gastric cancer progression. LncRNAs exert important roles in regulating various cancer behaviors. However, the functions and mechanisms of lncRNAs in angiogenesis remain largely unknown. Here we demonstrated that lncRNA PVT1 was upregulated and significantly associated with high-microvessel density and poor prognosis in gastric cancer. Through gain- and loss-of PVT1 expression, we found PVT1 could obviously induce angiogenesis within tumors, in addition to promoting tumor growth in vitro and in vivo. Mechanistically, PVT1 directly interacted with the signal transducer activator phospho-STAT3 in the nucleus, and increased its protein stability by protecting it from poly-ubiquitination and proteasome-dependent degradation. The binding of PVT1 activated the STAT3 signalling pathway, and successively elevated VEGFA expression to stimulate angiogenesis. The positive correlation of PVT1 and VEGFA expression was also verified in gastric cancer specimens, and high levels of PVT1 and VEGFA in combination frequently predicted shorter survival time. Moreover, we revealed that PVT1 was a STAT3-responsive lncRNA, as STAT3 could occupy the PVT1 promoter to facilitate its transcription. The positive feed-back loop of PVT1 and STAT3 continuously enhanced the oncogenic effects. Collectively, our study first elucidates the mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis, which provides promising target for developing new therapeutic strategy in gastric cancer.

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Acknowledgements

This study was supported by the Natural Science Foundation of China (81672378, 81201521, 81071994, 81672820, and 81400007), the Foundation from Science and Technology Commission of Shanghai (09XD1400800), and the National Major Scientific Instruments and Equipment Development Project of China (2013YQ15082909, 2012ZX10002012).

Funding:

This study was supported by the Natural Science Foundation of China (81672378, 81201521, 81071994, 81672820, and 81400007), the Foundation from Science and Technology Commission of Shanghai (09XD1400800), and the National Major Scientific Instruments and Equipment Development Project of China (2013YQ15082909, 2012ZX10002012).

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    Authors and Affiliations

    1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

      Jing Zhao, Peizhun Du, Yunyun Qin, Cheng’en Hu, Lunxiu Qin & Guangjian Huang

    2. Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China

      Jing Zhao & Lunxiu Qin

    3. Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China

      Peng Cui, Jing Wu & Wenhong Zhang

    4. Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China

      Zhongwen Zhou

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    These authors contributed equally: Jing Zhao, Peizhun Du, Peng Cui.

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    Zhao, J., Du, P., Cui, P. et al. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene 37, 4094–4109 (2018). https://doi.org/10.1038/s41388-018-0250-z

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