title: TLR4 activates the β-catenin pathway to cause intestinal neoplasia.
abstract: Colonic bacteria have been implicated in the development of colon cancer. We have previously demonstrated that toll-like receptor 4 (TLR4), the receptor for bacterial lipopolysaccharide (LPS), is over-expressed in humans with colitis-associated cancer. Genetic epidemiologic data support a role for TLR4 in sporadic colorectal cancer (CRC) as well, with over-expression favoring more aggressive disease. The goal of our study was to determine whether TLR4 played a role as a tumor promoter in sporadic colon cancer. Using immunofluorescence directed to TLR4, we found that a third of sporadic human colorectal cancers over-express this marker. To mechanistically investigate this observation, we used a mouse model that over-expresses TLR4 in the intestinal epithelium (villin-TLR4 mice). We found that these transgenic mice had increased epithelial proliferation as measured by BrdU labeling, longer colonic crypts and an expansion of Lgr5+ crypt cells at baseline. In addition, villin-TLR4 mice developed spontaneous duodenal dysplasia with age, a feature that is not seen in any wild-type (WT) mice. To model human sporadic CRC, we administered the genotoxic agent azoxymethane (AOM) to villin-TLR4 and WT mice. We found that villin-TLR4 mice showed an increased number of colonic tumors compared to WT mice as well as increased β-catenin activation in non-dysplastic areas. Biochemical studies in colonic epithelial cell lines revealed that TLR4 activates β-catenin in a PI3K-dependent manner, increasing phosphorylation of β-catenin(Ser552), a phenomenon associated with activation of the canonical Wnt pathway. Our results suggest that TLR4 can trigger a neoplastic program through activation of the Wnt/β-catenin pathway. Our studies highlight a previously unexplored link between innate immune signaling and activation of oncogenic pathways, which may be targeted to prevent or treat CRC.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Leonard Miller School of Medicine, Miami, Florida, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Santaolalla
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Sussman
authors.forename: Jose R
authors.initials: JR
authors.lastname: Ruiz
authors.forename: Julie M
authors.initials: JM
authors.lastname: Davies
authors.forename: Cristhine
authors.initials: C
authors.lastname: Pastorini
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: España
authors.forename: John
authors.initials: J
authors.lastname: Sotolongo
authors.forename: Oname
authors.initials: O
authors.lastname: Burlingame
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Bejarano
authors.forename: Sakhi
authors.initials: S
authors.lastname: Philip
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Ahmed
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ko
authors.forename: Ramanarao
authors.initials: R
authors.lastname: Dirisina
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D051197:Toll-Like Receptor 4; C026615:villin; D019869:Phosphatidylinositol 3-Kinases