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

• Published in: Cancer communications (London, England) Vol. 38; no. 1; pp. 1 - 10
• Main Authors: Wang, Liang, Bi, Xi‐wen, Zhu, Yu‐jia, He, Ying‐zhi, Lai, Qiu‐yu, Xia, Zhong‐jun, Cai, Qing‐qing
• Format: Journal Article
• Language: English
• Published: London BioMed Central 19.10.2018; Wiley
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Cell Proliferation - physiology; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Epstein–Barr virus; Humans; Interleukin-2 receptor alpha; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Latent membrane protein 1; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; Lymphoma, Extranodal NK-T-Cell - metabolism; Lymphoma, Extranodal NK-T-Cell - pathology; Natural Killer T-Cells - metabolism; Natural killer/T-cell lymphoma; Original; Up-Regulation; Natural killer/T-cell lymphoma; Epstein–Barr virus; Interleukin-2 receptor alpha; Latent membrane protein 1
• ISSN: 2523-3548; 2523-3548
• DOI: 10.1186/s40880-018-0334-8

Background Natural killer/T‐cell lymphoma (NKTCL) is a highly aggressive non‐Hodgkin lymphoma often resistant to chemotherapy. Serum level of soluble IL‐2 receptor α (IL‐2Rα) is elevated in NKTCL patients and correlates significantly with treatment response and survival. In the current study we examined the potential role of IL‐2Rα by over‐expressing IL‐2Rα in representative cell lines. Methods Levels of IL‐2Rα were 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‐2Rα in both NK‐92 and SNK‐6 cells. The biological effects of these genes on proliferation, apoptosis, cell cycle distribution, and chemosensitivity were analyzed. Results Expression of IL‐2Rα was significantly higher in SNK‐6 cells than in NK‐92 cells. Expressing LMP1 in NK‐92 cells remarkably up‐regulated IL‐2Rα levels, whereas selective inhibitorss of the proteins in the MAPK/NF‐κB pathway significantly down‐regulated IL‐2Rα. IL‐2Rα overexpression 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‐2Rα antibody. Conclusions Our results suggest that LMP1 activates the MAPK/NF‐κB pathway in NKTCL cells, up‐regulating IL‐2Rα expression. IL‐2Rα overexpression promotes growth and chemoresistance in NKTCL, making this interleukin receptor a potential therapeutic target.