An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice
- 2 April 2012
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (4), 1519-1528
- https://doi.org/10.1172/jci59743
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.This publication has 48 references indexed in Scilit:
- Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent mannerBlood, 2011
- Regulator of Calcineurin 1 Controls Growth Plasticity of Adult PancreasGastroenterology, 2010
- Ras Activity in Acinar Cells Links Chronic Pancreatitis and Pancreatic CancerClinical Gastroenterology and Hepatology, 2009
- Ras Activity Levels Control the Development of Pancreatic DiseasesGastroenterology, 2009
- Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic KrasBiochemical and Biophysical Research Communications, 2009
- Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor SuppressorPLoS Biology, 2008
- Robust acinar cell transgene expression of CreErT via BAC recombineeringgenesis, 2008
- Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivoJCI Insight, 2007
- Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult MiceCancer Cell, 2007
- Both p16 Ink4a and the p19 Arf -p53 pathway constrain progression of pancreatic adenocarcinoma in the mouseProceedings of the National Academy of Sciences of the United States of America, 2006