ArticleThe Journal of clinical investigation2012
An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 184 papers, 3 of them syntheses that pooled it.
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Who cites it
184 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Research trends and knowledge structure of pancreatic cancer and type 2 diabetes mellitus research: a two-decade CiteSpace analysis.Frontiers in endocrinology · 2026Pooled it
- Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review.Signal transduction and targeted therapy · 2023Pooled it
- Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.Pancreas · 2018Pooled it
- Elevation in multiple serum inflammatory biomarkers predicts survival of pancreatic cancer patients with inoperable disease.Journal of gastrointestinal cancer · 2014Trial
- Dynamic remodeling of the pancreas immune landscape in obesity.Nature communications · 2026Article
- The Role of Salivary Microbiota in Pancreatic Cancer: From Screening to Tumor Progression and Treatment Response.Biomedicines · 2026Review
- Quantitative 3D histology reveals localized immune remodeling during early pancreatic cancer progression.Cell press blue · 2026Article
- Intratumoral microbiome and pancreatic cancer: an enabling hallmark and path to novel treatments?British journal of cancer · 2026Review
- CYLD Limits Neutrophil-Driven Psoriatic Inflammation.Inflammation · 2026Article
- Leveraging the germ layer development patterns to predict prognosis and identify MEST as a novel therapeutic target in glioma.Cancer cell international · 2026Article
- A Narrative Review on Unravelling Bacterial-Mediated Carcinogenesis and Possible Alternative Treatment Strategies.BioMed research international · 2026Review
- Gut microbiome and nutritional strategies in gastrointestinal cancers: Clinical implications and therapeutic perspectives.World journal of clinical oncology · 2025Review
- Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.bioRxiv : the preprint server for biology · 2025Article
- Inhibition of CD45-specific phosphatase activity restores the differentiation potential of aged mesenchymal stromal cells: implications in regenerative medicine.Biological research · 2025Article
- Article
- The dual role of gut microbiota in pancreatic cancer: new insights into onset and treatment.Therapeutic advances in medical oncology · 2025Review
- The development of pancreatic cancer is accompanied by significant changes in the immune response in genetically predisposed mice.Frontiers in oncology · 2025Article
- Coxsackievirus and adenovirus receptor expression facilitates enteroviral infections to drive the development of pancreatic cancer.Nature communications · 2024Article
- Adaptor protein Abelson interactor 1 in homeostasis and disease.Cell communication and signaling : CCS · 2024Review
- KRAS-Driven Tumorigenesis and KRAS-Driven Therapy in Pancreatic Adenocarcinoma.Molecular cancer therapeutics · 2024Review
124 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors.
Funding
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.
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