IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma

Background:Natural killer/T-cell lymphoma(NKTCL)is a highly aggressive non-Hodgkin lymphoma often resistant to chemotherapy.Serum level of soluble IL-2 receptorα(IL-2Rα)is elevated in NKTCL patients and correlates signifi-cantly with treatment response and survival.In the current study we examined the potential role of IL-2Rαby over-expressing IL-2Rαin representative cell lines.Methods:Levels of IL-2Rαwere evaluated in the human natural killer cell line NK-92 and the NKTCL cell line SNK-6.Lentiviral vectors were used to express latent membrane protein 1(LMP1)in NK-92 cells,and IL-2Rαin both NK-92 and SNK-6 cells.The biological effects of these genes on proliferation,apoptosis,cell cycle distribution,and chemosensitiv-ity were analyzed.Results:Expression of IL-2Rαwas significantly higher in SNK-6 cells than in NK-92 cells.Expressing LMP1 in NK-92 cells remarkably up-regulated IL-2Rαlevels,whereas selective inhibitorss of the proteins in the MAPK/NF-κB pathway significantly down-regulated IL-2Rα.IL-2Rαoverexpression in SNK-6 cells promoted cell proliferation by altering cell cycle distribution,and induced resistance to gemcitabine,doxorubicin,and asparaginase.These effects were reversed by an anti-IL-2Rαantibody.Conclusions:Our results suggest that LMP1 activates the MAPK/NF-κB pathway in NKTCL cells,up-regulating IL-2Rαexpression.IL-2Rαoverexpression promotes growth and chemoresistance in NKTCL,making this interleukin receptor a potential therapeutic target.

LMP1 Immunohistochemistry in Non-Hodgkin’s Lymphoma of Sudanese Cases

Back ground: Non-Hodgkin’s lymphoma (NHL) with its different subtypes is strongly related to Epstein Bar virus (EBV) infection mainly Burkitt’s lymphoma in Africa. Studies proved the role of EBV in tumor-genesis and linked it to prognosis and therapy of patients. Objectives: To determine the frequency of EBV in non-Hodgkin lymphomas using EBV latent membrane protein 1 (EBV-LMP1) immunohistochemical stain. Methods: This cross-sectional study was conducted at radio-isotope centre of Khartoum (2012-2014). A total of 75 cases of non-Hodgkin lymphoma paraffin embedded sections were stained for EBV LMP1 antibody. Data were analyzed by SPSS 16 and statistical cross linking of the results of immune staining with other data was done. Results: Out of 75 patients of non Hodgkin’s lymphoma (74.7%) were males. EBV-LMP1 Immune-staining was positive in (17.3%) with predominance of Burkitt’s lymphoma (33.3%), followed by diffuse large B cell lymphoma (17.9%). Conclusion: Burkitt’s lymphoma expressed the highest percentage of non-Hodgkin’s lymphoma positive cases (46.2%) out of the total (17.3%) positive cases. Different methods need to be used in studying Burkitt’s lymphoma expression of EBV and its effects on the treatment and prognosis of cases.

Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop

The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma(NPC), which is prevalent in southern China and closely related to Epstein-Barr virus(EBV) infection.How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1(LMP1) promoted cyclophilin A(CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis.CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection.