Critical and distinct roles of cell type–specific NF-κB2 in lung cancer
Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao
Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao
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Research Article Oncology

Critical and distinct roles of cell type–specific NF-κB2 in lung cancer

Abstract

Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type–dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB–targeted therapy against this deadliest cancer.

Authors

Fan Sun, Yadong Xiao, Steven D. Shapiro, Zhaoxia Qu, Gutian Xiao

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Figure 7

NF-κB2 regulation of AMs involving RelA inhibition.

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NF-κB2 regulation of AMs involving RelA inhibition. (A) qPCR showing dec...
(A) qPCR showing decreased Arg1 and increased Nos2 in the AMs of urethane-treated NF-κB2–deficient mice (n = 5). (B) IF analysis showing decreased Arg1 and increased NOS2 in the AMs of urethane-treated NF-κB2–deficient mice (n = 5). (C) qPCR showing decreased Vegfa (WT, n = 3; NF-κB2–/–, n = 5), but increased Il1b (n = 5), Il12b (n = 4), and Tnf (WT, n = 5; NF-κB2–/–, n = 4) in the AMs of urethane-treated NF-κB2–deficient mice. (D) qPCR showing different increases in Nos2 and Arg1 in NF-κB2–deficient and WT macrophages by lung tumor–conditioned medium (TCM), respectively. (E) IF analysis showing increased NOS2 and decreased Arg1 proteins in NF-κB2–deficient (n = 6) compared with WT (n = 6) macrophages cultured with TCM. (F) In vitro tumor cell killing assays showing enhanced tumor-killing ability of NF-κB2–deficient macrophages activated by TCM (n = 3). (G) IF analysis showing higher nuclear RelA in NF-κB2–deficient macrophages cultured with TCM (n = 4). (H) qPCR showing increased Hif1a and decreased Hif2a in NF-κB2–deficient macrophages induced by TCM culture (n = 3). (I) ChIP assays showing increased RelA and HIF1α at the Nos2 promoter in NF-κB2–deficient macrophages induced by TCM culture (n = 3). (J) ChIP assays showing decreased HIF2α binding to 2 hypoxia-response element (HRE) sites within the Arg1 promoter in NF-κB2–deficient macrophages induced by TCM culture (n = 3). Scale bars: 10 μm (B, E, and G). Data are presented as mean ± SEM. *P < 0.05; **P < 0.01 by 2-tailed, unpaired Student’s t test (A, C, F, and H–J). NS, not statistically significant.