EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization

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.

Identification of the alpha linolenic acid metabolism-related signature associated with prognosis and the immune microenvironment in nasopharyngeal carcinoma

“…Peng et al found that the microRNA-18a from M2 Macrophages could inhibit TGFBR3, further promoting NPC progression and tumor growth by the TGF-b signaling pathway (42). In addition, Zhang et al found that EB virus-induced ATR activation could accelerate NPC growth through M2-type macrophage polarization (43). Meanwhile, our results indicated that the low-risk patients were more sensitive to immunotherapy, indicating the underlying potential of our model for individualized treatment.…”

Single-cell analysis revealed that IL4I1 promoted ovarian cancer progression

“…Macrophages were reclustered to two subtypes that revealed the heterogeneity of macrophages. Studies revealed that TAMs could promote tumorigenesis through TGFβ signaling in tumor cells [ 33 – 35 ]. In present study, we observed some carcinogenesis genes such as TGFBR2 were highly expressed in S0.…”

Periodontal Pathogens Promote Oral Squamous Cell Carcinoma by Regulating ATR and NLRP3 Inflammasome

“…It was found in this study that P. gingivalis and F. nucleatum could promote the proliferation of HSC-3 cells in vitro and increase the arrest of S phase cells, similar to previous studies ( 22 , 23 ). The increase of S phase arrest of cell cycle increased the replication pressure of tumor cells, stimulated the probability of genome mismatch, and promoted the progress of the tumor ( 24 ). It was also found in this study that P. gingivalis and F. nucleatum can promote the expression of cyclin D1, which can promote the cell cycle G1–S transition, leading to the increase of S phase arrest.…”