Carcinoembryonic antigen interacts with TGF-{beta} receptor and inhibits TGF-{beta} signaling in colorectal cancers.
Carcinoembryonic antigen interacts with TGF-{beta} receptor and inhibits TGF-{beta} signaling in colorectal cancers.
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DOI：
10.1158/0008-5472.can-10-1073
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Mishra L
中科院分区：
文献类型：
--
作者：
Li Y;Cao H;Jiao Z;Pakala SB;Sirigiri DN;Li W;Kumar R;Mishra L
作为结直肠癌的肿瘤标志物，CEA增强癌细胞的转移潜力。CEA作为细胞间粘附分子起作用，并且在多种人类癌症中上调。然而，CEA介导转移的分子机制仍有待了解。TGF-β信号传导调节肿瘤抑制和转移，并且还有助于刺激结肠直肠癌细胞中CEA的转录和分泌。然而，CEA是否反过来影响TGF-β功能以及CEA和TGF-β信号通路之间是否存在调节性串扰仍然未知。本文报道CEA直接与TGF-β受体相互作用，抑制TGF-β信号转导。用CEA特异性抗体或siRNA靶向CEA可挽救CEA升高的结肠直肠癌细胞系中的TGF-β应答，从而恢复TGF-β信号传导对增殖的抑制作用。CEA还在动物研究中增强结直肠癌细胞在局部定植和肝转移中的存活。我们的研究为CEA和TGF-β信号通路之间的相互作用提供了新的见解，并在放大结肠癌细胞向更具侵袭性表型的进展中建立了负反馈回路。这些发现为通过共靶向CEA促进TGF-β通路的肿瘤抑制作用来抑制结直肠癌细胞增殖提供了新的治疗机会。
As a tumor marker for colorectal cancers, CEA enhances the metastatic potential of cancer cells. CEA functions as an intercellular adhesion molecule and is up-regulated in a wide variety of human cancers. However, the molecular mechanisms by which CEA mediate metastasis remain to be understood. TGF-β signaling regulates both tumor suppression and metastasis, and also contributes to the stimulation of CEA transcription and secretion in colorectal cancer cells. However, it remains unknown whether CEA, in-turn, influences TGF-β functions and if a regulatory cross-talk exists between CEA and TGF-β signaling pathway. Here we report that CEA directly interacts with TGF-β receptor and inhibits TGF-β signaling. Targeting CEA with either CEA specific antibody or siRNA rescues TGF-β response in colorectal cancer cell lines with elevated CEA, thereby restoring the inhibitory effects of TGF-β signaling on proliferation. CEA also enhances the survival of colorectal cancer cells in both local colonization and liver metastasis in animal study. Our study provides novel insights into the interaction between CEA and TGF-β signaling pathway and establishes a negative feed-back loop in amplifying the progression of colon cancer cells to more invasive phenotypes. These findings offer new therapeutic opportunities to inhibit colorectal cancer cell proliferation by co-targeting CEA in promoting tumor inhibitory action of TGF-β pathway.