title: Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability.
abstract: STAT3 was recently reported to suppress tumor invasion in Apc(min)(/+) mice. We investigated the mechanisms by which STAT3 inhibits intestinal epithelial tumors using Apc(min)(/+)/Stat3(IEC-KO) mice (intestinal epithelial cell (IEC)-specific deletion of STAT3 in the Apc(min)(/+) background) to determine the role of STAT3 in carcinogenesis in vivo as well as colorectal cancer cell lines in vitro. To inhibit invasion of IEC tumors, STAT3 functions as a molecular adaptor rather than a transcription factor. Accordingly, the tumors in Apc(min)(/+)/Stat3(IEC-KO) mice undergo adenoma-to-carcinoma transition and acquire an invasive phenotype. Similarly, STAT3 knockdown in a colorectal cell line enhances IEC invasion. We demonstrate that STAT3 down-regulates SNAI (Snail-1) expression levels and hence suppresses epithelial-mesenchymal transition of colorectal cancer cells. Mechanistically, STAT3 facilitates glycogen synthase kinase (GSK) 3β-mediated degradation of SNAI by regulating phosphorylation of GSK3β. Our data identified a new role for STAT3 in the adenoma-to-carcinoma sequence of intestinal tumors.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093-0663, USA. j142lee@ucsd.edu
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Joanna C K
authors.initials: JC
authors.lastname: Kim
authors.forename: Shee-Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Christine
authors.initials: C
authors.lastname: Quinley
authors.forename: HyeRi
authors.initials: H
authors.lastname: Kim
authors.forename: Scott
authors.initials: S
authors.lastname: Herdman
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000473:pathology*; D049109:Cell Proliferation; D017931:DNA Primers; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C494087:Stat3 protein, mouse; D014157:Transcription Factors