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

J Clin Invest. 2012 Apr;122(4):1519-28. doi: 10.1172/JCI59743. Epub 2012 Mar 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / etiology*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Transformation, Neoplastic / genetics
  • Ceruletide / toxicity
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / physiology
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Enzyme Induction
  • Feedback, Physiological / physiology*
  • Gabexate / analogs & derivatives
  • Gabexate / toxicity
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knock-In Techniques
  • Genes, ras*
  • Humans
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / physiology
  • Inflammation / chemically induced
  • Inflammation / complications
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Transgenic
  • NF-kappa B / physiology*
  • Neoplasm Proteins / biosynthesis
  • Pancreas / metabolism
  • Pancreatic Neoplasms / etiology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatitis, Chronic / chemically induced
  • Pancreatitis, Chronic / genetics
  • Pancreatitis, Chronic / metabolism
  • Precancerous Conditions / chemically induced
  • Precancerous Conditions / genetics
  • Proto-Oncogene Proteins p21(ras) / biosynthesis
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • Sincalide / toxicity

Substances

  • Cyclooxygenase 2 Inhibitors
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Neoplasm Proteins
  • camostat
  • Gabexate
  • Ceruletide
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Sincalide