Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling
Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling
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DOI：
10.1016/j.ccr.2010.11.008
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发表时间：
2011-01-18
期刊：
影响因子：
50.3
通讯作者：
Taketo, Makoto Mark
中科院分区：
文献类型：
--
作者：
Sonoshita, Masahiro;Aoki, Masahiro;Taketo, Makoto Mark
转移是大多数癌症死亡的原因。在这里，我们表明，Aes（或Grg5）基因的功能作为一个内源性转移抑制因子。在小鼠和人类中，与原发性结肠肿瘤相比，肝转移瘤中Aes的表达降低。Aes通过将活性Rbpj转录复合物转化为不溶性核基质上的阻遏复合物来抑制Notch信号传导。在肿瘤细胞中，Notch信号由邻近血管上的配体触发，并刺激跨内皮迁移。Apc（Delta 716）肠息肉病小鼠中Aes的遗传缺失引起显著的肿瘤侵袭和内渗，其被Notch信号传导抑制所抑制。这些结果表明，抑制Notch信号传导可能是预防和治疗结肠癌转移的有希望的策略。
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(Delta 716) 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.