Nasopharyngeal carcinoma progression is mediated by EBER-triggered inflammation via the RIG-I pathway

• We ascertain the correlation between EBER and RIG-I expression from both NPC cell lines and clinical tissues data.
• We make it clear that EBERs (EBV encoded RNAs) could launch a chronic inflammation in vitro and in vivo.
• EBER triggered inflammation is verified to be critical to tumor progression in vivo.
• RIG-I-dependent NF-κB and IRF3 signaling pathways are involved in the EBER-triggered inflammatory response.
• EBER-triggered inflammatory cytokines potentiate TAM chemoattraction and polarization via RIG-I.

EBERs (EBER1 and EBER2) are suggested to be involved in cellular transformation and tumor growth. Cytoplasmic pattern recognition receptor-RIG-I, which is characterized by the recognition of viral dsRNAs, could efficiently trigger the downstream pathways of innate immunity. Although some previous reports have shown that EBERs and RIG-I associate with hematological malignancies, the role of EBERs-RIG-I signaling in solid tumors remains to be clarified. Here we demonstrate that EBER mediation of the inflammatory response via RIG-I contributes to NPC development in vitro and in vivo. We first verified that the expression level of RIG-I was associated with EBER transcription in a dose-dependent manner in NPC cells and specimens from NPC patients. Furthermore, pro-inflammatory cytokine transcription and release were sharply reduced after RIG-I knockdown compared with the control shRNA group in the presence of EBERs, accompanied by an attenuation of the NF-κB and MAPK signaling pathways. Consequently, the tumor burden was greatly alleviated in the RIG-I knockdown group in a xenograft model. In addition, macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP-1), which promote the maturation and attraction of tumor-associated macrophages, were stimulated upon the introduction of EBERs, and this upregulation conceivably led to the tumor-promoting subset transition of the macrophages. Taken together, our results reveal that EBERs could promote NPC progression through RIG-I-mediated cancer-related inflammation.