LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma

Abstract

The latent membrane protein-1 (LMP-1) is essential for Epstein-Barr virus (EBV)-induced nasal natural killer/T-cell lymphoma (NKTL). The aim of the present study was to evaluate the role of LMP-1 in NKTL. Two human EBV-positive NKTL cell lines (SNK-6 and SNT-8) were transfected with pcDNA3.1-LMP-1 or LMP-1 siRNA. Compared with the blank control, the cell apoptosis rates were decreased by 10.31 and 12.05% after pcDNA3.1-LMP-1 transfection and increased by 41.48 and 35.63% after lentiviral LMP-1 siRNA infection in the SNK-6 and SNT-8 cells. Survivin expression was induced by LMP-1, and the effect was attenuated by inhibitors of survivin, NF-κB and PI3K/Akt. Reduction in cell apoptosis by LMP-1 was also inhibited by inhibitors of survivin, NF-κB and PI3K/Akt. For the in vivo assay, tumor-bearing mice were established by subcutaneous injection with differentially treated SNT-8 cells into the back of the nude mice, and the tumor growth in the different groups was recorded. The results revealed that tumor formation and growth were also inhibited by treatment with survivin, NF-κB and PI3K/Akt inhibitors. Collectively, LMP-1-induced survivin expression inhibited cell apoptosis through the NF-κB and PI3K/Akt pathways, and survivin may be a new target for the treatment of NKTL induced by EBV.

Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency

“…Survivin is upregulated in many cancers, including EBV associated NPC, and during EBV immortalization of B-lymphocytes [48]. At least several EBV proteins have been implicated in the up regulation of Survivin, including EBNA1 [49] and LMP1 [50, 51]. Survivin is also a member of the chromosome passenger complex (CPC) that regulates Aurora B and Polo-like kinase 1 (PLK1) activity at kinetochores during mitosis [46].…”

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

“…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.…”

Molecular Pathogenesis of Peripheral T Cell Lymphoma

“…NKTL tumor cells display a latency II pattern, implying partial expression of viral proteins and micro-RNAs [54,55]. For example, latent membrane protein-1 (LMP-1), an EBV protein, induces expression of survivin, antagonizing apoptosis [56]. The miR-BART20-5p, a micro-RNA encoded by EBV, inhibits translation of TBX21 mRNA, rendering tumor cells resistant to p53-dependent apoptosis [57].…”