EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis

Abstract

Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BARTs), have been demonstrated to play fundamental roles in altering host cell metabolism to support nasopharyngeal carcinoma (NPC) pathogenesis. Yet, how do EBV infection and its encoded oncogenes facilitated the metabolic shifting and their roles in NPC carcinogenesis remains unclear. In this review, we will focus on delineating how EBV infection and its encoded oncoproteins altered the metabolic reprograming of infected cells to support their malignances. Furthermore, based on the understanding of the host's metabolic signaling alterations induced by EBV, we will provide a new perspective on the interplay between EBV infection and these metabolic pathways and offering a potential therapeutic intervention strategy in the treatment of EBV-associated malignant diseases.

Keywords: EBV infection; NPC pathogenesis; metabolic reprogramming; nasopharyngeal carcinoma; therapeutic strategies.

Figure 1

Activation of multiple signaling pathways that involved in glucose metabolism in NPC cells by EBV-encoded onco-products as well as the somatic-mutated genes identified in NPC. EBV-encoded latent gene product, LMP1, involves in regulation of glucose metabolism through multiple pathways including AMPK/mTOR, PI3K/AKT/mTOR, IKK/NF-κB, FGFR and cyclin D1 signaling. The common somatic mutations in NPC targeting to these multiple presented pathways are also shown to involve in glucose metabolism. EBV infection also regulates glucose metabolism through multiple transcription factors, like HIF-1α and c-Myc, that mediated glycolytic enzymes activation. EBV microRNA also involves in regulation of glucose metabolism in NPC.

Figure 2

Lactate produced by EBV enhanced aerobic glycolysis contributes to all the major steps in NPC pathogenesis. Lactate increases the expression of vascular endothelial growth factor (VEGF) stimulating angiogenesis, increases extracellular acidosis of tumor microenvironment to beneath the cancer cell motility and metastasis. Lactate is also involved in the ‘immune escape’ by decreasing monocyte migration and decreased activation of T cells as well as cytokine release. Finally, lactate is necessary for protecting cancer cells escape from apoptosis and resistance to therapy.