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

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric car-cinoma (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, HIF1 alpha, 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, HIF1 alpha, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1 alpha expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1 alpha 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 accumu-lation of HIF1 alpha under hypoxia. There was a positive feedback loop between HIF1 alpha 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.

Automated summary

This study found that EBV-encoded circular RNA LMP2A (ebv-circLMP2A) is expressed in EBV-associated gastric carcinoma (EBVaGC) and is associated with distant metastasis and poor prognosis. The study further demonstrated that ebv-circLMP2A is involved in angiogenesis and is positively correlated with the expression of MVD, HIF1 alpha, and VEGFA. Knockdown and overexpression experiments showed that ebv-circLMP2A regulates tube formation and migration of HUVECs and affects the expression of VEGFA and HIF1 alpha in cancer cells under hypoxia. Additionally, there is a positive feedback loop between HIF1 alpha and ebv-circLMP2A that promotes angiogenesis under hypoxia.