Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt 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-α). 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-α in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-α protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3β), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-α, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3β was elevated in the colonic mucosa of obese mice (P<.02). Moreover, β-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-α 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.

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Background: Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown.Methods: Concentrations of TNFa, IL1b, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined.Results: Plasma IL6 and TNFa were 1.4-to 3-fold elevated in obese subjects [body mass index (BMI) ! 34 kg/m 2 ] compared with the lean controls (P < 0.01). Among individuals with BMI ! 34 kg/m 2 colonic concentrations of IL6 and TNFa were 2-to 3-fold greater than in lean subjects (P < 0.03).In a general linear model, adjusted for NSAID use, colonic IL6 (partial r ¼ 0.41; P < 0.01) and TNFa (partial r ¼ 0.41; P ¼ 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (b ¼ À0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFkB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects.Conclusions: Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome.Impact: These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.

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