The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

Yongfa Zheng,Cong Chen,Changhu Li,Wei Ge,Liang Liu,Qin Huang,Dedong Cao,Ximing Xu,Pingpo Ming

doi:10.7717/peerj.3627

Abstract

Angiogenesis is an important factor contributing to the radioresistance of lung cancer. However, the associated mechanisms underlying radiotherapy-induced pro-angiogenesis are unclear. Here, we demonstrated that Extracellular vesicles (EVs) derived from cultured cells in vitro enhanced HUVEC proliferation and migration, and the enhancement effect became more obvious when HUVECs were treated with EV derived from A549 or H1299, two lung cancer cell lines. Additionally, the pro-angiogenesis effect induced by EV could be strengthened when the lung cancer cells were exposed to X-ray irradiation. Furthermore, we verified that the downregulation of PTEN plays a vital role in this process. By evaluating the changes in the levels of microRNAs(miRNAs) targeting PTEN in EV, we found that miR-23a was significantly upregulated and mediated a decrease in PTEN. A luciferase reporter gene transfer experiment demonstrated that PTEN was the direct target of miR-23a, and the kinetics of PTEN expression were opposite to those of miR-23a. Our results show that the miR-23a/PTEN pathway plays an important role in EV-induced angiogenesis. These findings implicate the miR-23a/PTEN axis as a novel therapeutic target for lung cancer radiotherapy.

Highlights

Lung cancer has one of the highest morbidity and mortality rates of all cancers and has a poor prognosis (Torre et al, 2012)
These data suggest that Extracellular vesicles (EVs) secreted by lung cancer cells can be successfully isolated and can be transferred to human umbilical vein endothelial cells (HUVECs) efficiently
Compared with HEK293-derived EVs, EVs secreted by lung cancer cells (A549 or H1299) promoted the proliferation of HUVECs, and the effect was enhanced when the cancer cells were exposed to 4 Gy X-ray irradiation. These results demonstrated that EVs derived from lung cancer cells enhanced the proliferation of HUVECs, and this effect was strengthened when the cells were exposed to X-ray irradiation

Summary

Introduction

Lung cancer has one of the highest morbidity and mortality rates of all cancers and has a poor prognosis (Torre et al, 2012). Molecular targeted therapies for lung cancer have demonstrated efficacy, but the 5-year survival rate of lung cancer patients continues to be dismal (Chaffer & Weinberg, 2011); it is urgent to elucidate the mechanisms of radiation resistance, and identify new therapeutic targets that will increase the cytotoxicity of radiotherapy. Radiation may induce abnormal expression of some miRNAs that may function as oncogenes (Verma & Lautenschlaeger, 2016). These changes may decrease the levels of lethal factors or tumor suppressors, and promote the proliferation of cancer cells. Identifying the mechanisms contributing to radiotherapy-induced metastasis will reduce the mortality rate and increase the disease-free survival of patients diagnosed with lung cancer

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Conclusion