Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1\u03b1-repressed microRNA-519d

Ting Xu,Dajiang Xiao

doi:10.1186/s13046-016-0480-2

Abstract

BackgroundOleuropein (OL) is a well-known anti-oxidative agent and is shown to reduce the hypoxia-inducible factor 1 α (HIF1α) protein expression after radiation. The current study investigated the effects of OL on radiation response in nasopharyngeal carcinoma (NPC).MethodsColony 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 HIF1α, miR-519d and PDRG1. Stable HIF1α or PDRG1 overexpression, and miR-519d downregulation were performed to test the radiation response both in vitro and in vivo.ResultsOL 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 HIF1α, and PDRG1 was a direct target of miR-519d. Overexpression of HIF1α or PDRG1, and downregulation of miR-519d abolished the radiation sensitizing effects of OL.ConclusionOur study hereby demonstrates OL is a radiation sensitizing agent in NPC both in vivo and in vitro. OL treatment reduces the activity of HIF1α-miR-519d-PDRG1 pathway, which is essential to the radiosensitizing effects of OL.

Highlights

Oleuropein (OL) is a well-known anti-oxidative agent and is shown to reduce the hypoxia-inducible factor 1 α (HIF1α) protein expression after radiation
OL enhances radiosensitivity of nasopharyngeal carcinoma (NPC) cells both in vitro and in vivo To investigate the effects of OL on radiation sensitivity, we performed colony formation assay in NPC cell lines HNE-1 and HONE-1 incubated with or without OL after irradiation
We investigated whether the decrease in miR519d expression by OL treatment was mediated by HIF1α

Summary

Introduction

Oleuropein (OL) is a well-known anti-oxidative agent and is shown to reduce the hypoxia-inducible factor 1 α (HIF1α) protein expression after radiation. The current study investigated the effects of OL on radiation response in nasopharyngeal carcinoma (NPC). Understanding the underlying mechanism of radiation resistance and developing the radiosensitive drugs are urgent needs for improving the local control and survival rate of advanced NPC patients. OL has been extensively reported as a potential anti-cancer reagent by many researchers [3]. A recently study showed OL could reduce the protein expression of hypoxia-inducible factor 1 α (HIF1α) [4], which is a major regulator of the radiation response in cancer cells. It is of great interest to investigate whether OL could exhibit a potential radiosensitizing effect on cancer cells

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Discussion

Conclusion