|Author||Sonoshita M, Aoki M, Fuwa H, Aoki K, Hosogi H, Sakai Y, Hashida H, Takabayashi A, Sasaki M, Robine S, Itoh K, Yoshioka K, Kakizaki F, Kitamura T, Oshima M, Taketo MM.|
|Title||Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling.|
Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.
|MeSH||Animals Benzodiazepinones / pharmacology Benzodiazepinones / therapeutic use Cell Line, Tumor Co-Repressor Proteins Colonic Neoplasms / drug therapy Colonic Neoplasms / metabolism Colonic Neoplasms / pathology* Down-Regulation / genetics Gene Expression / genetics Gene Silencing / physiology HCT116 Cells Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism Intestinal Polyposis / drug therapy Intestinal Polyposis / metabolism Intestinal Polyposis / pathology Ligands Liver Neoplasms / pathology Liver Neoplasms / secondary Lung Neoplasms / pathology Lung Neoplasms / prevention & control Lung Neoplasms / secondary Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Mutant Strains Mice, Nude Mice, Transgenic Models, Biological Neoplasm Invasiveness / genetics Neoplasm Invasiveness / pathology Neoplasm Invasiveness / prevention & control Neoplasm Metastasis / genetics Neoplasm Metastasis / pathology Neoplasm Metastasis / prevention & control Nuclear Matrix / metabolism Receptor, Notch1 / metabolism Receptors, Notch / antagonists & inhibitors Receptors, Notch / metabolism* Repressor Proteins / genetics Repressor Proteins / metabolism Signal Transduction / drug effects Signal Transduction / physiology* Stromal Cells / metabolism Transcription Factors / genetics Transcription Factors / metabolism* Transendothelial and Transepithelial Migration / physiology|
|WOS Category||ONCOLOGY CELL BIOLOGY|
|DNA material||pRBS-EGFP (RDB08039)|