Signaling pathways of EBV-induced oncogenesis

Abstract

Epstein-Barr virus (EBV) is closely associated with multiple human cancers. EBV-associated cancers are mainly lymphomas derived from B cells and T cells (Hodgkin lymphoma, Burkitt lymphoma, NK/T-cell lymphoma, and posttransplant lymphoproliferative disorder (PTLD)) and carcinomas derived from epithelial cells (nasopharyngeal carcinoma and gastric carcinoma). EBV can induce oncogenesis in its host cell by activating various signaling pathways, such as nuclear factor-κB (NF-κB), phosphoinositide-3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and transcription activator (JAK/STAT), mitogen-activated protein kinase (MAPK), transforming growth factor-β (TGF-β), and Wnt/β-catenin, which are regulated by EBV-encoded proteins and noncoding RNA. In this review, we focus on the oncogenic roles of EBV that are mediated through the aforementioned signaling pathways.

Keywords: Cancer; Epstein‐barr virus (EBV); Signaling pathway.

Fig. 1

EBV-induced oncogenesis through the NF-κB signaling pathway. LMP1 can enhance the activity of NF-κB, enter the nucleus to activate transcription and promote cell proliferation, migration and invasion. LMP1 can inhibit the expression of miRNA-203 through NF-κB, resulting in high expression of CDH6 and EMT. At the same time, LMP1 can also activate the IKK2/TPL2/JNK signaling axis, which is beneficial to the survival of LCL. The combination of LMP1 and p65 can activate hTERT and inhibit PINX1, which together promote cell immortalization. EBV-miRNA-BART13 inhibits NKIRAS2, thereby promoting cell proliferation, migration and invasion

Fig. 2

EBV-induced oncogenesis through the PI3K/AKT signaling pathway. LMP1 and LMP2A promote angiogenesis through the PI3K/AKT/HIF-1α/CCL5 signaling axis and the PI3K/AKT/mTOR/HIF-1α signaling axis, respectively. LMP1 inhibits PTEN through miRNA-21 and enhances the PI3K/AKT signaling pathway to promote the formation and proliferation of CSCs. EBV-miRNA-BART7-3P can also promote the high expression of β-catenin by inhibiting PTEN, leading to EMT

Fig. 3

EBV-induced oncogenesis through the JAK/STAT signaling pathway. When JAK is activated, it can phosphorylate STAT, and then dimeric STAT is exposed to the nuclear signal and enters the nucleus to participate in regulating gene expression. LMP1 can activate JAKs and then activate the STAT dimer, which promotes the corresponding transcriptional regulation in the nucleus and can provide feedback and enhance the regulation of its own expression. LMP1 enhances the transcription of AP-1 through JAK/STAT and promotes the expression of PD-L1 to avoid immune surveillance. LMP1 and LMP2A can activate HLX to inhibit apoptosis

Fig. 4

EBV-induced oncogenesis through the MAPK signaling pathway. LMP1 can activate ERK, JNK, and p38 and reduce the expression of DUSP6 and DUSP8 to promote cell proliferation and enhance c-JUN to promote the occurrence of EMT. β1 integrin can promote the expression of LMP1 and activate FAK, which will promote cell proliferation. EBV-miRNA-BART13-3P and EBV-miRNA-BART22 inhibit the upstream and downstream MAPK pathways, promote EMT, and resist apoptosis, respectively

Fig. 5

EBV-induced oncogenesis through the TGF-β signaling pathway. After TGF-β is stimulated, it activates Smad2 and Smad3 and then combines with Smad4 to enter the nucleus to regulate transcription, inhibit cell proliferation signals, and promote apoptosis of injured cells. LMP2A and EBNA1 can destabilize Smad2, thereby inhibiting the proliferation-inhibiting signal produced by TGF-β. Cells that have been infected with EBV can promote the activation of the TGF-β signaling pathway and increase the expression of the BZLF1 gene, leading to increased viral replication and enhanced infectivity of EBV

Fig. 6

EBV-induced oncogenesis through the Wnt/β-catenin signaling pathway. The binding of Wnt and Frizzled protein will prompt LRP to phosphorylate and recruit protein complexes, and then these protein complexes will dissociate to release stable expression of β-catenin. Free β-catenin binds to TCF to activate the corresponding transcription after entering the nucleus. LMP2A inhibits the expression of GSK-3β through the PI3K/AKT signaling pathway, which interferes with the formation of protein complexes and promotes the accumulation of β-catenin in the nucleus to induce EMT. WTX can inhibit the expression of β-catenin, and LMP1 in transgenic mice will interfere with the inhibitory effect of WTX, resulting in the stable expression of β-catenin and leading to dysplasia