N,N′-Dinitrosopiperazine-Mediated AGR2 Is Involved in Metastasis of Nasopharyngeal Carcinoma

Yuejin Li,Jinping Lu,Chaojun Duan,Xiaowei Tang,Faqing Tang,Gongjun Tan,Zhenlin Zhang,Damao Huang,Na Liu,Zhengke Peng,Tiebang Kang

doi:10.1371/journal.pone.0092081

Abstract

Nasopharyngeal carcinoma (NPC) has a high metastatic character in the clinic, but its mechanism is not clear. As a carcinogen with organ specificity for the nasopharyngeal epithelium, N,N′-Dinitrosopiperazine (DNP) is involved in NPC metastasis. Herein, our data revealed that anterior gradient 2 (AGR2) was overexpressed in human NPC tissues, particularly in cervical lymph node metastatic NPC (LMNPC). High AGR2 expression was associated with NPC metastasis. Importantly, DNP induced AGR2 expression, and increased cell motility and invasion in the NPC cell line 6–10B. However, DNP-mediated cell motility and invasion was dramatically decreased when transfected with siRNA-AGR2. Further, AGR2 directly regulated cathepsin (CTS) B and D by binding them in vitro. These results indicate that DNP induces AGR2 expression, regulates CTSB and CTSD, increases cell motility and invasion, and promotes NPC tumor metastasis. Therefore, DNP-mediated AGR2 expression may be an important factor in prolific NPC metastasis.

Highlights

Nasopharyngeal carcinoma (NPC) is a common malignant cancer in southern China [1]
In endemic NPC, .95% are classified as undifferentiated World Health Organization (WHO) type III and is universally associated with the Epstein–Barr virus (EBV) [6], a strong etiological factor interacting with genetic predisposition [7], and dietary intake of preserved foods [8]
We investigated the mechanism of anterior gradient 2 (AGR2) in DNP-induced NPC invasion and metastasis

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a common malignant cancer in southern China [1]. Epidemiological investigations have revealed that the incidence of NPC has remained high in endemic regions, in Southeast Asia, with an incidence of 30–80 per 100,000 people per year in southern China [2]. In studies on Chinese populations in high-incidence regions, the relative risk of NPC is related to the region’s eating habits, with dietary intake of salt-preserved fish [8,9,10,11,12,13,14,15]. The process of salt preservation is inefficient and the food can become partially putrefied These foods accumulate significant levels of nitrosamines [16,17], which are known carcinogens [16,18,19]. DNP can induce malignant transformations of human embryonic nasopharyngeal epithelial cells [24]

Methods

Results

Conclusion