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  2. Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway

Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway

  • Cancer Lett. 2022 Feb 1;526:259-272. doi: 10.1016/j.canlet.2021.11.031.
Yu Du 1 Jing-Yue Zhang 1 Li-Ping Gong 1 Zhi-Ying Feng 1 Deyu Wang 1 Yu-Hang Pan 1 Li-Ping Sun 1 Jing-Yun Wen 2 Gao-Feng Chen 1 Jing Liang 1 Jian-Ning Chen 3 Chun-Kui Shao 4
Affiliations

Affiliations

  • 1 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: chjning@mail.sysu.edu.cn.
  • 4 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: shaochk@mail.sysu.edu.cn.
Abstract

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in Cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.

Keywords

Angiogenesis; Circular RNA; EBV; Gastric carcinoma; HIF1α.

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