Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer

被引:125
作者
Liu, Zhenhua [1 ,3 ,4 ]
Brooks, Ryan S. [1 ]
Ciappio, Eric D. [1 ,3 ]
Kim, Susan J. [4 ]
Crott, Jimmy W. [1 ,3 ,4 ]
Bennett, Grace [2 ,3 ]
Greenberg, Andrew S. [2 ,3 ]
Mason, Joel B. [1 ,3 ,4 ,5 ]
机构
[1] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Vitamins & Carcinogenesis Lab, Boston, MA 02111 USA
[2] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Obes & Metab Lab, Boston, MA 02111 USA
[3] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA
[4] Tufts Univ, Tufts Med Ctr, Ctr Canc, Boston, MA 02111 USA
[5] Tufts Univ, Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA
关键词
Obesity; TNF-alpha; Wnt pathway; Colon cancer; NECROSIS-FACTOR-ALPHA; ADIPOSE-TISSUE; GASTROINTESTINAL TUMORIGENESIS; CYCLIN D1; C-MYC; INFLAMMATION; CELLS; COLITIS; EXPRESSION; GROWTH;
D O I
10.1016/j.jnutbio.2011.07.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Writ pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF-alpha in the colon by 72% (1)=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-alpha protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3 beta), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-alpha, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3 beta was elevated in the colonic mucosa of obese mice (P<.02). Moreover, p-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF-alpha and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:1207 / 1213
页数:7
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