Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1α-repressed microRNA-519d

Background: Oleuropein (OL) is a well-known anti-oxidative agent and is shown to reduce the hypoxia-inducible factor 1 alpha (HIF1 alpha) protein expression after radiation. The current study investigated the effects of OL on radiation response in nasopharyngeal carcinoma (NPC). Methods: Colony formation assay was performed to compare the radiation response in vitro. Xenograft mouse model was used to study the OL effects on radiation in vivo. Chromatin immunoprecipitation and luciferase reporter assays were performed to identify the relations among HIF1 alpha, miR-519d and PDRG1. Stable HIF1 alpha or PDRG1 overexpression, and miR-519d downregulation were performed to test the radiation response both in vitro and in vivo. Results: OL strongly enhanced radiosensitivity of NPC cells both in vitro and in vivo. Chromatin immunoprecipitation and luciferase reporter assays suggested miR-519d was a direct target of HIF1 alpha, and PDRG1 was a direct target of miR-519d. Overexpression of HIF1 alpha or PDRG1, and downregulation of miR-519d abolished the radiation sensitizing effects of OL. Conclusion: Our study hereby demonstrates OL is a radiation sensitizing agent in NPC both in vivo and in vitro. OL treatment reduces the activity of HIF1 alpha-miR-519d-PDRG1 pathway, which is essential to the radiosensitizing effects of OL.