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TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia

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 T...

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Autores principales: Santaolalla, Rebeca, Sussman, Daniel A., Ruiz, Jose R., Davies, Julie M., Pastorini, Cristhine, España, Cecilia L., Sotolongo, John, Burlingame, Oname, Bejarano, Pablo A., Philip, Sakhi, Ahmed, Mansoor M., Ko, Jeffrey, Dirisina, Ramanarao, Barrett, Terrence A., Shang, Limin, Lira, Sergio A., Fukata, Masayuki, Abreu, Maria T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653932/
https://www.ncbi.nlm.nih.gov/pubmed/23691015
http://dx.doi.org/10.1371/journal.pone.0063298
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author Santaolalla, Rebeca
Sussman, Daniel A.
Ruiz, Jose R.
Davies, Julie M.
Pastorini, Cristhine
España, Cecilia L.
Sotolongo, John
Burlingame, Oname
Bejarano, Pablo A.
Philip, Sakhi
Ahmed, Mansoor M.
Ko, Jeffrey
Dirisina, Ramanarao
Barrett, Terrence A.
Shang, Limin
Lira, Sergio A.
Fukata, Masayuki
Abreu, Maria T.
author_facet Santaolalla, Rebeca
Sussman, Daniel A.
Ruiz, Jose R.
Davies, Julie M.
Pastorini, Cristhine
España, Cecilia L.
Sotolongo, John
Burlingame, Oname
Bejarano, Pablo A.
Philip, Sakhi
Ahmed, Mansoor M.
Ko, Jeffrey
Dirisina, Ramanarao
Barrett, Terrence A.
Shang, Limin
Lira, Sergio A.
Fukata, Masayuki
Abreu, Maria T.
author_sort Santaolalla, Rebeca
collection PubMed
description 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.
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spelling pubmed-36539322013-05-20 TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia Santaolalla, Rebeca Sussman, Daniel A. Ruiz, Jose R. Davies, Julie M. Pastorini, Cristhine España, Cecilia L. Sotolongo, John Burlingame, Oname Bejarano, Pablo A. Philip, Sakhi Ahmed, Mansoor M. Ko, Jeffrey Dirisina, Ramanarao Barrett, Terrence A. Shang, Limin Lira, Sergio A. Fukata, Masayuki Abreu, Maria T. PLoS One Research Article 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. Public Library of Science 2013-05-14 /pmc/articles/PMC3653932/ /pubmed/23691015 http://dx.doi.org/10.1371/journal.pone.0063298 Text en © 2013 Santaolalla et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Santaolalla, Rebeca
Sussman, Daniel A.
Ruiz, Jose R.
Davies, Julie M.
Pastorini, Cristhine
España, Cecilia L.
Sotolongo, John
Burlingame, Oname
Bejarano, Pablo A.
Philip, Sakhi
Ahmed, Mansoor M.
Ko, Jeffrey
Dirisina, Ramanarao
Barrett, Terrence A.
Shang, Limin
Lira, Sergio A.
Fukata, Masayuki
Abreu, Maria T.
TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title_full TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title_fullStr TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title_full_unstemmed TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title_short TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia
title_sort tlr4 activates the β-catenin pathway to cause intestinal neoplasia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653932/
https://www.ncbi.nlm.nih.gov/pubmed/23691015
http://dx.doi.org/10.1371/journal.pone.0063298
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