Carcinoembryonic Antigen Interacts with TGF-β Receptor and Inhibits TGF-β Signaling in Colorectal Cancers

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.