An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice
Jaroslaw Daniluk, … , Baoan Ji, Craig D. Logsdon
Jaroslaw Daniluk, … , Baoan Ji, Craig D. Logsdon
Published March 12, 2012
Citation Information: J Clin Invest. 2012;122(4):1519-1528. https://doi.org/10.1172/JCI59743.
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Research Article Oncology

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Abstract

Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB–mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

Authors

Jaroslaw Daniluk, Yan Liu, Defeng Deng, Jun Chu, Haojie Huang, Sebastian Gaiser, Zobeida Cruz-Monserrate, Huamin Wang, Baoan Ji, Craig D. Logsdon

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Figure 2

Cerulein administration led to the development of chronic pancreatitis and PanINs and prolonged elevated Ras activity only in the presence of mutant K-Ras.

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Cerulein administration led to the development of chronic pancreatitis a...
The CCK analog cerulein was injected using a scheme known to induce acute inflammation in the pancreas (Supplemental Figure 1). Pancreata from control littermates recovered from the acute effects of these injections and were histologically normal by day 14 (A, original magnification, ×100). In contrast, acinar-Ras animals showed a depletion of acinar cells, sustained edema, and inflammation 2 weeks after the first series of cerulein (Cer) treatments (B, original magnification, ×100; inset, ×400). By day 28, the pancreata from acinar-Ras mice showed abundant fibrosis and PanINs (C, original magnification, ×100; inset, ×400). Pancreatic ductal adenocarcinoma developed in acinar-Ras mice 8 months after cerulein treatments (D, original magnification, ×100; inset, ×400). For Ras activity assays, animals were sacrificed without treatment (week 0), 2 weeks after one series of cerulein injections (week 2), and 2 weeks after a second series of cerulein injections (week 4). Cerulein treatments caused a transient increase in signaling in littermate controls but a sustained and increasing level of Ras activity in acinar-Ras mice (E) (*P < 0.05 compared with controls; n = 8 animals).