Abstract

Chronic inflammation induced by persistent viruses infection plays an essential role in tumor progression, which influenced on the interaction between the tumor cells and the tumor microenvironment. Our earlier study showed that ATR, a key kinase participant in single-stranded DNA damage response (DDR), was obviously activated by Epstein–Barr virus (EBV) in nasopharyngeal carcinoma (NPC). However, how EBV-induced ATR activation promotes NPC by influencing inflammatory microenvironment, such as tumor-associated macrophages (TAMs), remains elusive. In this study, we showed that EBV could promote the expression of p-ATR and M2-type TAMs transformation in clinical NPC specimens. The expression of p-ATR and M2-type TAMs were closely correlated each other and involved in TNM stage, lymph node metastasis and poor prognosis of the patients. In addition, the expression levels of CD68+CD206+, Arg1, VEGF, and CCL22 were increased in EB+ CNE1 cells, and decreased when ATR was inhibited. In the nude mice, EBV-induced ATR activation promoted subcutaneous transplanted tumor growth, higher expression of Ki67 and lung metastasis via M2-type TAMs recruitment. Experimental data also showed that the polarization of M2, the declined tumor necrosis factor-α (TNF-α) and increased transforming growth factor-β (TGF-β) were associated with ATR. Meanwhile, ATR activation could promote PPAR-δ and inhibited c-Jun and p-JNK expression, then downregulate JNK pathway. Collectively, our current study demonstrated the EBV infection could activate the ATR pathway to accelerate the transition of TAMs to M2, suggesting ATR knockdown could be a potential effective treatment strategy for EBV-positive NPC.

Highlights

  • In recent years, it has been reported that 20% of the tumors are caused by microorganisms, and the virus play a great important role in tumorigenesis

  • Previous studies have shown that[13,14], Hepatitis B Virus (HBV) and human papillomavirus (HPV)-infected tumor cells can secrete a large number of chemokines and cytokines, and promote the transformation of macrophages to M2, hinting that viral infection might play an important role in the macrophage M2-type polarization

  • Epstein–Barr virus (EBV) infection-induced ATR activation and M2-type Tumor-associated macrophages (TAMs) transformation in clinical nasopharyngeal carcinoma (NPC) specimens To determine whether EBV infection elevated the level of p-ATR and CD68+/CD206+, immunohistochemistry was performed in 28 NPC and 24 nasopharyngeal inflammation (NPI) specimens

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Summary

Introduction

It has been reported that 20% of the tumors are caused by microorganisms, and the virus play a great important role in tumorigenesis. Zhang et al Cell Death and Disease (2020)11:742 accumulation and DNA fragmentation, change other signaling pathways to promote the tumor development[5,6]. Previous studies have shown that[13,14], Hepatitis B Virus (HBV) and human papillomavirus (HPV)-infected tumor cells can secrete a large number of chemokines and cytokines (such as IL-4, IL-2, IL-10, etc.), and promote the transformation of macrophages to M2, hinting that viral infection might play an important role in the macrophage M2-type polarization. ATR mutations lead to the decreased T cell recruitment, stimulate the increase in the number of M2 macrophages associated with tumor invasion and promote melanoma growth[18], indicating that endogenous ATR mutations results in M2 TAMs accumulation

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