TLR4 Activates the β-catenin pathway to cause intestinal neoplasia

Santaolalla, Rebeca, Sussman, Daniel A., Ruiz, Jose R., Davies, Julie M., Pastorini, Cristhine, Espana, 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, Masayuku and Abreu, Maria T. (2013) TLR4 Activates the β-catenin pathway to cause intestinal neoplasia. PLoS One, 8 5: e63298. doi:10.1371/journal.pone.0063298

Author Santaolalla, Rebeca
Sussman, Daniel A.
Ruiz, Jose R.
Davies, Julie M.
Pastorini, Cristhine
Espana, 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, Masayuku
Abreu, Maria T.
Title TLR4 Activates the β-catenin pathway to cause intestinal neoplasia
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-05-14
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pone.0063298
Open Access Status DOI
Volume 8
Issue 5
Start page e63298
Total pages 15
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Formatted 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID CA137869
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 15 Nov 2016, 22:15:18 EST by Julie Davies on behalf of Mater Research Institute-UQ