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TNF‐α induced alterations in the Wnt signaling cascade: a potential mechanism for obesity‐associated colorectal tumorigenesis
Author(s) -
Brooks Ryan S,
Ciappio Eric D,
Bennett Grace,
Crott Jimmy W,
Mason Joel B,
Liu Zhenhua
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb384
Subject(s) - wnt signaling pathway , carcinogenesis , colorectal cancer , tumor necrosis factor alpha , medicine , endocrinology , cancer research , downregulation and upregulation , signal transduction , cancer , biology , microbiology and biotechnology , biochemistry , gene
Epidemiological studies consistently implicate obesity as an important risk factor for several types of cancer, and the data is particularly compelling for colorectal cancer. However, the underlying mechanism is not defined. This study investigated whether Wnt ‐signaling, a critical pathway in colorectal carcinogenesis, is upregulated by the inflammatory cytokine, TNF‐α, which has been found to be elevated in obesity. Obesity was induced in C57BL6 mice using a high‐fat diet (60% kcal). TNF‐α protein in the colon, determined by ex vivo culture of the colon followed by ELISA of the media, was significantly elevated (p<0.05) in obese mice. Phospho‐GSK3β, which is an important intermediary in Wnt signaling and which has been reported to be induced by TNF‐α, was elevated by immunohistochemistry in the colonic mucosa of obese mice. Significant elevations of β‐catenin protein as well as increased c‐myc mRNA were evident in the colonic mucosa of the obese mice (p<0.05), and are also consistent with Wnt activation. These results demonstrate that obesity elevates colonic levels of TNF‐α and provide evidence that it may activate Wnt ‐signaling in that organ. (This material is based on work supported by the USDA under agreement no. 58‐1950‐7‐707 and by the Prevent Cancer Foundation)