LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway

Abstract

Abstract. Nasal natural killer T-cell lymphoma (NKTL) is a highly malignant tumor that is closely associated with EpsteinBarr virus (EBV) infection. Latent membrane protein 1 (LMP1) is encoded by EBV and plays an important role in EBV-induced cell transformation. Therefore, we assessed the function of LMP1 as a stimulant of NKTL progression and the underlying mechanism. A human EBV-positive NKTL cell line (SNK-6) was transfected with pcDNA3.1-LMP1, LV-LMP1 shRNA or LV-eukaryotic translation initiation factor 4E (eIF4E)-shRNA. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the proliferation of SNK-6 cells, and cell migration and invasion were analyzed by Transwell chamber assay. Flow cytometry was used to analyze the cell cycle and apoptosis. The results showed LMP1 was highly expressed in SNK-6 cells compared with control groups. Following pretreatment with LMP1 shRNA, the proliferation of SNK-6 cells was inhibited and resulted in a G0/G1 phase arrest. A reduction in invasion and migration was also observed. LMP1 silencing promoted cell apoptosis. Further mechanistic analysis suggested that LMP1 overexpression induced the expression of eIF4E, while eIF4E-shRNA dramatically attenuated the increase in cell proliferation, invasion, migration and the inhibition of apoptosis triggered by LMP-1 upregulation. Moreover, the effect of LMP1 on eIF4E expression was mediated by the NF-κB pathway. Therefore, this finding may provide a potential target against NKTL.

A neutralized human LMP1-IgG inhibits ENKTL growth by suppressing the JAK3/STAT3 signaling pathway

“…Because LMP1-Fab has exhibited tumor-inhibitory potentiality in NPC [16, 17] and LMP1 plays important roles in ENKTL progression [9, 14, 15], whole LMP1-IgG is theoretically supposed to exert more significant anti-tumor effectiveness in ENKTL. Bearing this in mind, we performed a series of experiments to detect the tumor-inhibitory role of LMP1-IgG in vitro .…”

“…In NPC for example, LMP1 preserves the cancer stemness of NPC cells by activating the PI3K/AKT pathway [33]; LMP1 critically mediates transformation of nasopharyngeal epithelial cells and facilitates FGF2/FGFR1 signaling activation in the EBV-driven pathogenesis of NPC [34]. In lymphoma, LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of a receptor tyrosine kinase and makes an important contribution to promote the oncogenic effects of EBV [35]; LMP1 has also been reported to aggravate malignant cell function, induce surviving expression and inhibit cell apoptosis through NF-κB and PI3K/Akt signaling pathways [9, 36]. All the above data support that LMP1-IgG demonstrates dramatic ability to inhibit cell growth and accelerate cell apoptosis.…”

“…Latent membrane protein 1 (LMP1), a substantial oncoprotein encoded by EBV, has been suggested to have multiple malignant functions in the development and progression of EBV-related ENKTL [9, 10]. Identification of LMP1 expression is drawing attention as a favorable target for ENKTL treatment [11, 12].…”

Genetics and genomics of extranodal natural killer/T cell lymphoma: from etiology to treatment

“…NF-κB has critical biological implications in the growth, proliferation, differentiation, and regulation of lymphocytes that are regarded as vital pathogenetic factors in lymphomas [53] . Expression of RelA and cRel, two canonical molecules of the NF-κB pathway in NKTCL, suggested abnormal activation of canonical NF-κB pathway [13] .…”

New developments in the pathology of malignant lymphoma. A review of the literature published from September 2015–December 2015

“…Latent membrane protein 1 (LMP1) is encoded by EBV and plays an important role in EBV-induced cell transformation. Therefore, Sun et al [ 12 ] assessed the function of LMP1 as a stimulant of NKTL progression and the underlying mechanism. A human EBV-positive NKTL cell line (SNK-6) was transfected with pcDNA3.1-LMP1, LV-LMP1 shRNA, or LV-eukaryotic translation initiation factor 4E (eIF4E)-shRNA.…”