EBV-miR-BART1-5P activates AMPK/mTOR/HIF1 pathway via a PTEN independent manner to promote glycolysis and angiogenesis in nasopharyngeal carcinoma

Abnormal metabolism and uncontrolled angiogenesis are two important characteristics of malignant tumors. The occurrence of both events involves many key molecular changes including miRNA. However, EBV encoded miRNAs are rarely mentioned as capable of regulating tumor metabolism and tumor angiogenesis. Here, we reported that one of the key miRNAs encoded by EBV, EBV-miR-Bart1-5P, can significantly promote nasopharyngeal carcinoma (NPC) cell glycolysis and induces angiogenesis in vitro and in vivo. Mechanistically, EBV-miR-Bart1-5P directly targets the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1) and consequently regulates the AMPK/mTOR/HIF1 pathway which impelled NPC cell anomalous aerobic glycolysis and angiogenesis, ultimately leads to uncontrolled growth of NPC. Our findings provide new insights into metabolism and angiogenesis of NPC and new opportunities for the development of targeted NPC therapy in the future.
Author summary The Epstein-Barr virus (EBV), the first reported human tumor virus found to encode miRNAs, which closely related to malignant progression of tumors. In our study, we have observed that EBV-miR-BART1-5P, an EBV-BARTs encoded miRNA, promotes glycolysis and induces angiogenesis in NPC. Interestingly, we showed that overexpression of EBV-miR -BART1-5P and restored PTEN at the same time, did not completely reverse the phenotypes of glycolysis, angiogenesis and proliferation, suggesting that EBV-miR-BART1-5P can mediate glycolysis and induction angiogenesis by a PTEN-independent manner. Further mechanism exploration demonstrated that EBV-miR-BART1-5P has important roles in cancer cell glucose metabolism and angiogenesis by inhibiting AMPKα1 and PTEN, which provides a molecular basis for the regulation of AMPK/mTOR/HIF1 and PTEN/FAK, Shc, AKT pathways, respectively.