title: Transforming growth factor-beta suppresses nonmetastatic colon cancer through Smad4 and adaptor protein ELF at an early stage of tumorigenesis.
abstract: Although transforming growth factor-beta (TGF-beta) 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 beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta 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-beta signaling in the suppression of early colon cancer.
authors.affiliation: Laboratory of GI Developmental Biology, Department of Surgery, Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Varalakshmi
authors.initials: V
authors.lastname: Katuri
authors.forename: Radhika
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Franz
authors.initials: F
authors.lastname: Fogt
authors.forename: Robert
authors.initials: R
authors.lastname: Redman
authors.forename: Girish
authors.initials: G
authors.lastname: Anand
authors.forename: Anan
authors.initials: A
authors.lastname: Said
authors.forename: Thomas
authors.initials: T
authors.lastname: Fishbein
authors.forename: Michael
authors.initials: M
authors.lastname: Zasloff
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051901:Smad4 Protein; D013049:Spectrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta
chemical_list: D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D013049:Spectrin