Mouse tissues that undergo neoplastic progression after K-Ras activation are distinguished by nuclear translocation of phospho-Erk1/2 and robust tumor suppressor responses.

Abstract

Mutation of K-Ras is a frequent oncogenic event in human cancers, particularly cancers of lungs, pancreas, and colon. It remains unclear why some tissues are more susceptible to Ras-induced transformation than others. Here, we globally activated a mutant oncogenic K-Ras allele (K-Ras(G12D)) in mice and examined the tissue-specific effects of this activation on cancer pathobiology, Ras signaling, tumor suppressor, DNA damage, and inflammatory responses. Within 5 to 6 weeks of oncogenic Ras activation, mice develop oral and gastric papillomas, lung adenomas, and hematopoietic hyperproliferation and turn moribund. The oral, gastric, and lung premalignant lesions display activated extracellular signal-regulated kinases (Erk)1/2 and NF-κB signaling as well as activated tumor suppressor and DNA damage responses. Other organs such as pancreas, liver, and small intestine do not exhibit neoplastic progression within 6 weeks following K-Ras(G12D) activation and do not show a potent tumor suppressor response. Even though robust Erk1/2 signaling is activated in all the tissues examined, the pErk1/2 distribution remains largely cytoplasmic in K-Ras(G12D)-refractory tissues (pancreas, liver, and intestines) as opposed to a predominantly nuclear localization in K-Ras(G12D)-induced neoplasms of lung, oral, and gastric mucosa. The downstream targets of Ras signaling, pElk-1 and c-Myc, are elevated in K-Ras(G12D)-induced neoplastic lesions but not in K-Ras(G12D)-refractory tissues. We propose that oncogenic K-Ras-refractory tissues delay oncogenic progression by spatially limiting the efficacy of Ras/Raf/Erk1/2 signaling, whereas K-Ras-responsive tissues exhibit activated Ras/Raf/Erk1/2 signaling, rapidly form premalignant tumors, and activate potent antitumor responses that effectively prevent further malignant progression.

• Authors: Neha Parikh, Ryan L Shuck, Thuy-Ai Nguyen, Alan Herron, Lawrence A Donehower
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 10 Issue 6 Pg. 845-55 (Jun 2012) ISSN: 1557-3125 [Electronic] United States
• PMID: 22532587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2012 AACR

Chemical References

• Antineoplastic Agents, Hormonal
• Tumor Suppressor Proteins
• Tamoxifen
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Active Transport, Cell Nucleus (drug effects)
• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Blotting, Western
• Cell Nucleus (metabolism)
• Cell Transformation, Neoplastic (drug effects, genetics, metabolism)
• Disease Progression
• Humans
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Fluorescence
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Models, Biological
• Mutation
• Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-raf (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, genetics)
• Tamoxifen (pharmacology)
• Transcriptional Activation (drug effects, genetics)
• Tumor Suppressor Proteins (genetics, metabolism)