Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis.
Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis.
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Bcl-3 通过稳定 Smad3 在乳腺癌肺转移过程中调节 TGFβ 信号传导
DOI：
10.1038/cddis.2016.405
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发表时间：
2016-12-01
影响因子：
9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Chen X;Cao X;Sun X;Lei R;Chen P;Zhao Y;Jiang Y;Yin J;Chen R;Ye D;Wang Q;Liu Z;Liu S;Cheng C;Mao J;Hou Y;Wang M;Siebenlist U;Eugene Chin Y;Wang Y;Cao L;Hu G;Zhang X
乳腺癌中的转化生长因子β（TGFβ）信号传导与肺转移选择性相关。然而，其潜在机制仍不清楚。在此，我们发现IκB家族成员Bcl-3在TGFβ信号转导中起关键调节作用，从而调节乳腺癌肺转移。Bcl-3表达与乳腺癌患者的无转移生存率显著相关。Bcl-3基因缺失抑制了乳腺癌细胞的体外迁移和侵袭，也抑制了乳腺癌的体内肺转移。Bcl-3是参与乳腺癌肺转移的下游TGFβ信号转导基因表达所必需的。Bcl-3基因敲低可促进TGFβ处理后Smad 3的降解，但对Smad 2无影响。Bcl-3可与Smad 3结合，阻止Smad 3蛋白的泛素化和降解。这些结果表明，Bcl-3作为一个有前途的目标，以防止乳腺癌肺转移。
Transforming growth factor beta (TGFβ) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the IκB family, serves as a critical regulator in TGFβ signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGFβ signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGFβ treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis.