TY - JOUR
T1 - Transforming growth factor-β suppresses nonmetastatic colon cancer through Smad4 and adaptor protein ELF at an early stage of tumorigenesis
AU - Tang, Yi
AU - Katuri, Varalakshmi
AU - Srinivasan, Radhika
AU - Fogt, Franz
AU - Redman, Robert
AU - Anand, Girish
AU - Said, Anan
AU - Fishbein, Thomas
AU - Zasloff, Michael
AU - Reddy, E. Premkumar
AU - Mishra, Bibhuti
AU - Mishra, Lopa
PY - 2005/5/15
Y1 - 2005/5/15
N2 - Although transforming growth factor-β (TGF-β) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a β-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-β to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf +/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-β signaling in the suppression of early colon cancer.
AB - Although transforming growth factor-β (TGF-β) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a β-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-β to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf +/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-β signaling in the suppression of early colon cancer.
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U2 - 10.1158/0008-5472.CAN-04-4585
DO - 10.1158/0008-5472.CAN-04-4585
M3 - Article
C2 - 15899814
AN - SCOPUS:20144378766
SN - 0008-5472
VL - 65
SP - 4228
EP - 4237
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -