Abstract
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.
Highlights
The development of malignant tumors is divided into several stages: malignant transformation of cells, clonal proliferation of transformed cells, local infiltration and distant metastasis
Further mechanism exploration demonstrated that Epstein-Barr virus (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
To validate the roles of BART1 in nasopharyngeal carcinoma (NPC) glycometabolism, we detected the secretion of lactate and the consumption of glucose by transiently transfecting BART1-3P and BART1-5P mimics into 7 cell lines (2 EBV-negative NPC cell lines and 5 EBV-negative epithelial cell lines) respectively
Summary
The development of malignant tumors is divided into several stages: malignant transformation of cells, clonal proliferation of transformed cells, local infiltration and distant metastasis. An abnormal supply of energy and sustained angiogenesis, two of the ten characteristics of tumor development [1], maintain the growth during the different stages of the cancer. They play an important role in cancer progression, including regulation of cancer growth, invasion and metastasis [2]. Due to the rapid proliferation of cancer cells, hypoxia occurs to which cancer cells adapt by upregulating their glycolysis. This leads to an increased acid production, which leads to a significant decrease in the local extracellular pH. In a variety of tumors, including nasopharyngeal carcinoma (NPC), the molecular mechanism leading to abnormal aerobic glycolysis remains obscure
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