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Supplemental Table 1 from Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma

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posted on 2023-04-03, 19:44 authored by Deng-Ke Li, Xing-Rui Chen, Li-Na Wang, Jia-Hong Wang, Yue-Ting Wen, Zi-Ying Zhou, Ji-Ke Li, Jing-Xian Liu, Lin-Bo Cai, Shui-Sheng Zhong, Xiao-Ming Lyu, Faleti Oluwasijibomi Damola, Min-Ying Li, Jing-Jing Zhang, Yu-Mei Zeng, Qian-Li Wang, Qian-Bing Zhang, Hao Lyu, Xiao-Yan Fu, Wei Wang, Xin Li, Zhong-Xi Huang, Kai-Tai Yao

Correlation between the clinicopathological features and EBV status

Funding

Sanming Project of Medicine in Shenzhen

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Guangzhou Basic and Applied Basic Research Foundation

Medical Scientific Research Foundation of Guangdong Province of China

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ARTICLE ABSTRACT

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.

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