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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.
AuthorsRebeca Santaolalla, Daniel A Sussman, Jose R Ruiz, Julie M Davies, Cristhine Pastorini, Cecilia L España, John Sotolongo, Oname Burlingame, Pablo A Bejarano, Sakhi Philip, Mansoor M Ahmed, Jeffrey Ko, Ramanarao Dirisina, Terrence A Barrett, Limin Shang, Sergio A Lira, Masayuki Fukata, Maria T Abreu
JournalPloS one (PLoS One) Vol. 8 Issue 5 Pg. e63298 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23691015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Microfilament Proteins
  • Toll-Like Receptor 4
  • villin
  • Phosphatidylinositol 3-Kinases
Topics
  • Adenoma (genetics, metabolism, pathology)
  • Animals
  • Carcinogenesis
  • Colorectal Neoplasms (genetics, metabolism, pathology)
  • DNA Damage
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intestinal Mucosa (metabolism, pathology)
  • Intestinal Neoplasms (genetics, metabolism, pathology)
  • Mice
  • Microfilament Proteins (genetics)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Signal Transduction
  • Toll-Like Receptor 4 (genetics, metabolism)

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