title: 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.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Daniluk
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Defeng
authors.initials: D
authors.lastname: Deng
authors.forename: Jun
authors.initials: J
authors.lastname: Chu
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gaiser
authors.forename: Zobeida
authors.initials: Z
authors.lastname: Cruz-Monserrate
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002108:Ceruletide / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction; D004952:Esters; D025461:Feedback, Physiological / Q000502:physiology*; D016670:Gabexate / Q000031:analogs & derivatives / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055879:Gene Knock-In Techniques; D011905:Genes, ras; D006146:Guanidines; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000502:physiology*; D012844:Sincalide / Q000633:toxicity
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D006146:Guanidines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; C034532:camostat; D016670:Gabexate; D002108:Ceruletide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D012844:Sincalide