BPIFB1 (LPLUNC1) inhibits radioresistance in nasopharyngeal carcinoma by inhibiting VTN expression

Fang Wei,Zhaoyang Zeng,Le Tang,Jiayou Luo ,Lei Shi,Xiaoling Li,Xiayu Li,Wei Xiong,Fang Xiong,Qianxi Ni,Yong Li,Yi He,Xiang Chen,Guiyuan Li,Can Guo,Wenling Zhang,Zhaojian Gong,Cong Peng,Qianjin Liao,Yingfen Wu

doi:10.1038/s41419-018-0409-0

Abstract

Bactericidal/permeability-increasing-fold-containing family B member 1 (BPIFB1, previously named LPLUNC1) is highly expressed in the nasopharynx and significantly downregulated in nasopharyngeal carcinoma (NPC). Low expression is also associated with poor prognosis in patients with NPC. Radiotherapy is a routine treatment for NPC; however, radioresistance is a major cause of treatment failure. Thus, we aimed to investigate the role of BPIFB1 in the radioresponse of NPC. Colony formation and cell survival results showed that BPIFB1 sensitized NPC cells to ionizing radiation. VTN, a previously identified BPIFB1-binding protein, was shown to induce cell proliferation and survival, G2/M phase arrest, DNA repair, activation of the ATM-Chk2 and ATR-Chk1 pathways, and anti-apoptotic effects after exposure to radiation, facilitating NPC cell radioresistance. However, BPIFB1 inhibited this VTN-mediated radioresistance, ultimately improving NPC radiosensitivity. In conclusion, this study is the first to demonstrate the functions of BPIFB1 and VTN in the NPC radioresponse. Our findings indicated that promoting BPIFB1 expression and targeting VTN might represent new therapeutic strategies for NPC.

Highlights

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck malignancy associated with remarkable geographic and racial differences[1,2]; it is rare in most parts of the world, but occurs relatively frequently in Southeast Asia and southern China[3]
Re-expression of BPIFB1 sensitized NPC cells to ionizing radiation (IR) Our previous study showed that lower levels of BPIFB1 were correlated with poor prognosis in patients with NPC11
The results showed that the ability to form survival foci in NPC cells was significantly suppressed by BPIFB1 overexpression, and this inhibition was pronounced at 4 and 6 Gy in CNE2 (Fig. 1a, b) and HONE1 (Supplementary Fig. 1a, b) cells

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck malignancy associated with remarkable geographic and racial differences[1,2]; it is rare in most parts of the world, but occurs relatively frequently in Southeast Asia and southern China[3]. NPC is relatively sensitive to ionizing radiation (IR), and radiotherapy is routine and the only curative treatment for this type of cancer[5]. Radiotherapy can control local NPC and is associated with a positive outcome in early stages, a high proportion of patients still experience radiation resistance, which is the major cause of local recurrence and distant metastasis, resulting in treatment failure[6,7]. The malignant behavior of residual cells after irradiation and the associated underlying mechanisms are still unclear.

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Conclusion