Epstein-Barr Virus encoded LMP1 regulates cyclin D1 promoter activity by nuclear EGFR and STAT3 in CNE1 cells

Yang Xu,Ya Cao,Bin Yan,Ying Shi,Ling Chen,Yongguang Tao,Xuli Liu,Qi Yuan

doi:10.1186/1756-9966-32-90

Abstract

The principal Epstein–Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1) is strongly associated with nasopharyngeal carcinoma (NPC), a prevalent cancer in China. The epidermal growth factor receptor (EGFR) is important in carcinogenesis, as it is a ubiquitously expressed receptor tyrosine kinase. Signal transducer and activator of transcription 3 (STAT3) is a master transcriptional regulator in proliferation and apoptosis. Our previous study demonstrated that the nuclear EGFR could bind to the cyclin D1 promoter directly in the presence of LMP1, and the correlation between EGFR and STAT3 in NPC remains to be further explored. Here, we have shown that the interaction of EGFR and STAT3 increased in the nucleus in the presence of LMP1. LMP1 promoted both EGFR and STAT3 binding to the promoter region of cyclin D1, in turn, enhancing the promoter activity of cyclin D1. Furthermore, we demonstrated that both transcriptional activity and mRNA levels of cyclin D1 were decreased by small molecule interference of EGFR and STAT3 activity. These findings may provide a novel linkage between the EGFR and STAT3 signaling pathways and the activation of cyclin D1 by LMP1 in the carcinogenesis of NPC.

Highlights

Epstein-Barr virus (EBV) is a ubiquitous herpes virus that is linked to multiple malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, gastric cancer esophageal cancer cervical cancer and prostate cancer and nasopharyngeal carcinoma (NPC) [1,2,3,4,5,6,7,8,9]
Latent membrane protein 1 (LMP1) promoted the interaction of epidermal growth factor receptor (EGFR) with Signal transducer and activator of transcription 3 (STAT3) in NPC cells To investigate the possible interaction of EGFR and STAT3 in NPC cells, co-immunoprecipitation with immunoblot analysis was performed
LMP1 activated the activity of cyclin D1 promoter by the EGFR and STAT3 pathways Because cyclin D1 contains both EGFR and STAT3 binding sites adjacent within three nucleotides[31], we addressed whether nuclear accumulation and the interaction between EGFR and STAT3 at the cyclin D1 promoter was under the regulation of the oncoprotein LMP1

Summary

Introduction

Epstein-Barr virus (EBV) is a ubiquitous herpes virus that is linked to multiple malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, gastric cancer esophageal cancer cervical cancer and prostate cancer and nasopharyngeal carcinoma (NPC) [1,2,3,4,5,6,7,8,9]. We showed that nuclear EGFR could bind to the cyclin D1 promoter directly and transactivate the cyclin D1 promoter by LMP1 in NPC Many factors such as the epidermal growth factor, the DNA damage factor, ultraviolet irradiation, radiation and cetuximab increase EGFR translocation into the nucleus [24,25,26,27,28,29]. These findings clearly indicate that EGFR may act as a new factor that directly target genes related to cellular transformation, cell cycle regulation, DNA damage repair and replication

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Conclusion