TY - JOUR
T1 - Suppression of colon cancer metastasis by aes through inhibition of notch signaling
AU - Sonoshita, Masahiro
AU - Aoki, Masahiro
AU - Fuwa, Haruhiko
AU - Aoki, Koji
AU - Hosogi, Hisahiro
AU - Sakai, Yoshiharu
AU - Hashida, Hiroki
AU - Takabayashi, Arimichi
AU - Sasaki, Makoto
AU - Robine, Sylvie
AU - Itoh, Kazuyuki
AU - Yoshioka, Kiyoko
AU - Kakizaki, Fumihiko
AU - Kitamura, Takanori
AU - Oshima, Masanobu
AU - Taketo, Makoto Mark
N1 - Funding Information:
We thank H. Kikuchi and Y. Mouri for excellent technical assistance, T. Honjo for plasmids and suggestions, T. Sudo for microarray analyses, Y. Yui and T. Tanaka for time-lapse microphotography, O. Takahashi for high-magnification fluorescence microphotography, S. Stifani for anti-panTLE antibody, H. Sasaki for Hedgehog reporters, T. Ishikawa, H. Miyoshi, A. Deguchi, S. Arimura, S. Yamashita, I. Okazaki, T. Okazaki, K. Okawa, C. Takahashi, T. Tomita, and Y. Morohashi for helpful discussions, S. Takahashi for microinjection of ES cells into blastcysts, N. Copeland, N. Jenkins, J. Takeda, and K. Yusa for biologicals and suggestions for the recombineering system. We also thank P. Vogt, To. Kitamura, M. Okabe, M. Kitagawa, and S. Kirkland for providing vectors pBSfi-AU1-TLE1, pMX-IRES-EGFP, pCX, Maml1 cDNA and HCA7 cells, respectively. This work was supported by grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and by Jeannik M. Littlefield-AACR Grant in Metastatic Colon Cancer Research.
PY - 2011/1/18
Y1 - 2011/1/18
N2 - 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 ApcΔ716 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.
AB - 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 ApcΔ716 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.
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U2 - 10.1016/j.ccr.2010.11.008
DO - 10.1016/j.ccr.2010.11.008
M3 - Article
C2 - 21251616
AN - SCOPUS:78651446926
SN - 1535-6108
VL - 19
SP - 125
EP - 137
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
