title: CD137 ligand-mediated reverse signaling inhibits proliferation and induces apoptosis in non-small cell lung cancer.
abstract: CD137 ligand (CD137L), a member of the tumor necrosis factor superfamily, is expressed on antigen-presenting cells and also on various tumor cells. Crosslinking of CD137L transmits signals that evoke different cellular responses in a variety of tumor cells. This study was designed to investigate signaling pathways activated by CD137L and its physiologic role in the progression of NSCLC. We investigated the expression of CD137L in tissues from 102 cases of human non-small cell lung cancer (NSCLC) using immunohistochemistry and analyzed the correlation with clinicopathological features using Fisher's exact test and overall survival using Kaplan-Meier curves and the log-rank test. The effect of CD137L reverse signaling induced by recombinant human CD137-Fc protein on NSCLC cell lines was assessed using proliferation and apoptosis assays, flow cytometry and Western blotting. Positive CD137L expression was observed in 53/102 (52.0%) of the NSCLC samples and correlated with early TNM stage (P = 0.046), well-differentiated tumors (P = 0.009) and better overall survival (P = 0.004). Moreover, induction of CD137L reverse signaling using CD137-Fc inhibited proliferation and induced apoptosis and cell cycle arrest in H1650 cells, which express high levels of CD137L; CD137L reverse signaling had no significant effects in PC9 cells, which express low levels of CD137L. In addition, CD137L reverse signaling-induced apoptosis occurred via activation of the intrinsic pathway and depended on phosphorylation of JNK. This study demonstrates a hitherto unrecognized role for CD137L reverse signaling in the development of NSCLC and indicates that CD137L has potential as a novel therapeutic target in NSCLC.
authors: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
authors: Yingying
authors: Y
authors: Qian
authors: Dong
authors: D
authors: Pei
authors: Ting
authors: T
authors: Cheng
authors: Changling
authors: C
authors: Wu
authors: Xiaolin
authors: X
authors: Pu
authors: Xiaofeng
authors: X
authors: Chen
authors: Yiqian
authors: Y
authors: Liu
authors: Hong
authors: H
authors: Shen
authors: Weiwei
authors: W
authors: Zhang
authors: Yongqian
authors: Y
authors: Shu
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism*; D000328:Adult; D000368:Aged; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016019:Survival Analysis; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000494:pharmacology
chemical_list: D053330:4-1BB Ligand; C505974:TNFSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
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