NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function

Abstract

NF-κB is generally believed to be pro-tumorigenic. Here, we report a tumor-suppressive function for NF-κB1, the prototypical member of NF-κB. While NF-κB1 down-regulation is associated with high lung cancer risk in humans and poor patient survival, NF-κB1 deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor suppressive function of NF-κB1 is independent of its classical role as an NF-κB factor, but instead through stabilization of the Tpl2 kinase. NF-κB1 deficient tumors exhibit "normal" NF-κB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-κB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-κB1 deficient lung tumor cells. Remarkably, Tpl2 knockout mice resemble NF-κB1 knockouts in urethane-induced lung tumorigenesis. Mechanistic studies indicate that p105/Tpl2 signaling is required for suppressing urethane-induced lung damage and inflammation, and activating mutations of the K-Ras oncogene. These studies reveal an unexpected, NF-κB-independent but Tpl2-depenednt role of NF-κB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.

Myeloid STAT3 Promotes Lung Tumorigenesis by Transforming Tumor Immunosurveillance into Tumor-Promoting Inflammation

“…Mouse and human lung tissue histology and IHC were performed as described (32, 33). Antibodies used are listed in Supplementary Table S1.…”

“…Logistic regression analysis was used to compare the pulmonary inflammation in lung cancer patients between high and low myeloid STAT3 activation groups. Gehan-Breslow-Wilcoxon test and log-rank test were used to compare overall patient survival between high and low myeloid STAT3 activation groups (32). In addition to conventional P values ( P ), we also provided sex- and tumor stage–adjusted P values ( P adj ) for those human studies.…”

Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-κB/IL-6/STAT3 signaling

“…As described previously [65], Student's t test (two tailed) was used to assess significance of differences between two groups, and p values < 0.05 and 0.01 were considered statistically significant and highly statistically significant, and indicated by * and **, respectively.…”

Murine Bronchoalveolar Lavage

“…Pulmonary chronic inflammation plays a critical role in lung cancer initiation and progression. To clarify the underlying mechanism of inflammation in lung tumorigenesis, a basic BAL protocol in mice is used in our laboratory to determine the pulmonary immune response (Qu et al ., 2015; Zhou et al ., 2015; Sun et al ., 2016; Zhou et al ., 2017). …”