Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma
| Autor: | Min-Ying Li, Zi-Ying Zhou, Zhong-Xi Huang, Qian-Li Wang, Li-Na Wang, Yu-Mei Zeng, Xin Li, Xiaoming Lyu, Xiao-Yan Fu, Kaitai Yao, Hao Lyu, Jing-Xian Liu, Dengke Li, Qianbing Zhang, Yue-Ting Wen, Lin-Bo Cai, Wei Wang, Faleti Oluwasijibomi Damola, Shui-Sheng Zhong, Jia-Hong Wang, Xing-Rui Chen, Jing-Jing Zhang, Ji-Ke Li |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Epstein-Barr Virus Infections Vascular Endothelial Growth Factor C Mice Nude medicine.disease_cause Malignancy Metastasis Mice Downregulation and upregulation hemic and lymphatic diseases Cell Line Tumor otorhinolaryngologic diseases medicine Tumor Microenvironment Animals Humans Lymphangiogenesis Molecular Biology Protein kinase B Nasopharyngeal Carcinoma biology business.industry medicine.disease Epstein–Barr virus Up-Regulation stomatognathic diseases Oncology Nasopharyngeal carcinoma Lymphatic Metastasis Cancer research biology.protein Antibody business |
| Zdroj: | Molecular cancer research : MCR. 20(1) |
| ISSN: | 1557-3125 |
| Popis: | 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. Implications: 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. |
| Databáze: | OpenAIRE |
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