TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia

Rebeca 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

Research output: Contribution to journalArticle

55 Scopus citations

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-cateninSer552, 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.

Original languageEnglish (US)
Article numbere63298
JournalPloS one
Volume8
Issue number5
DOIs
StatePublished - May 14 2013

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Santaolalla, R., Sussman, D. A., Ruiz, J. R., Davies, J. M., Pastorini, C., España, C. L., Sotolongo, J., Burlingame, O., Bejarano, P. A., Philip, S., Ahmed, M. M., Ko, J., Dirisina, R., Barrett, T. A., Shang, L., Lira, S. A., Fukata, M., & Abreu, M. T. (2013). TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia. PloS one, 8(5), [e63298]. https://doi.org/10.1371/journal.pone.0063298