Carcinoembryonic antigen interacts with TGF-{beta} receptor and inhibits TGF-{beta} signaling in colorectal cancers.
As a tumor marker for colorectal cancers, carcinoembryonic antigen (CEA) enhances the metastatic potential of cancer cells. CEA functions as an intercellular adhesion molecule and is upregulated in a wide variety of human cancers. However, the molecular mechanisms by which CEA mediates metastasis remain to be understood. Transforming growth factor-β (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 the 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 feedback 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 cotargeting CEA in promoting tumor-inhibitory action of the TGF-β pathway.
Li
Ying
Y
Department of Gastroenterology, Hepatology and Nutrition, M.D. Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA.
Cao
Hong
H
Jiao
Zhongxian
Z
Pakala
Suresh B
SB
Sirigiri
Divijendra Natha Reddy
DN
Li
Wenpin
W
Kumar
Rakesh
R
Mishra
Lopa
L
D002272:Carcinoembryonic Antigen / Q000378:metabolism* / Q000627:therapeutic use*; D002455:Cell Division; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017931:DNA Primers; D016259:Genes, myc; D006801:Humans; D018895:Microsatellite Repeats / Q000502:physiology; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
D002272:Carcinoembryonic Antigen; D017931:DNA Primers; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta