The RON receptor tyrosine kinase is a potential therapeutic target in Burkitt lymphoma.
BACKGROUND
Aberrant expression of the RON receptor tyrosine kinase is associated with tumor progression and carcinogenesis. The aims of this study were to determine the role and functional mechanisms of RON in Burkitt lymphoma (BL) and to document its potential as a therapeutic target.


METHODS
RON expression was determined in BL cell lines by western blot analysis and examined in human lymphoma specimens by both western blotting and immunohistochemistry. The correlation between RON expression and Epstein-Barr virus (EBV) infection was investigated. Raji cells were treated with the Zt/f2 anti-RON mAb and cell viability, colony formation, apoptosis and cell cycle arrest were measured in vitro using cell proliferation assays, colony-forming assays and flow cytometry. Downregulation of RON by Zt/f2 was validated in mice bearing Raji cell xenografts.


RESULTS
Immunohistostaining showed a high frequency of RON (+) cells in BL tissues and RON expression strongly correlated with EBV positivity. RON downregulation significantly decreased cell proliferation and colony formation via promotion of apoptosis and cell cycle arrest in Raji cells. The in vivo study showed that RON knockdown inhibits the tumorigenic potential of Raji cells in nude mice.


CONCLUSIONS
RON acts as an oncogene in the carcinogenesis and progression of BL and is therefore a potential target for therapeutic intervention.
Department of Hematology, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China.
Xiangmin
X
Tong
Xuewu
X
Zhang
Jian
J
Fan
Yin
Y
Tong
Shuangshuang
S
Li
Jie
J
Jin
Hangping
H
Yao
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
Burkitt lymphoma; RON; mechanism; monoclonal antibody; oncogenic signal transduction; receptor tyrosine kinase; targeted therapy