Location: Dietary Prevention of Obesity-related Disease ResearchTitle: Genetic ablation of tumor necrosis factor-alpha attenuates colonic Wnt-signaling associated with obesity
|GUO, CHI - University Of Massachusetts, Amherst|
|KIM, SUSAN - Tufts University|
|FREDERICK, ARMINA-LYN - University Of Massachusetts, Amherst|
|LI, JINCHAO - University Of Massachusetts, Amherst|
|JIN, YU - University Of Massachusetts, Amherst|
|MASON, JOEL - Tufts University|
|LIU, ZHENHUA - University Of Massachusetts, Amherst|
Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/19/2019
Publication Date: 11/23/2019
Citation: Guo, C., Kim, S.J., Frederick, A., Li, J., Jin, Y., Zeng, H., Mason, J.B., Liu, Z. 2019. Genetic ablation of tumor necrosis factor-alpha attenuates colonic Wnt-signaling associated with obesity. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2019.108302.
Interpretive Summary: Colon cancer is a major public health issue in the US, with approximately 137,000 new cases and 50,000 deaths per year. Obesity has emerged as one of the leading environmental risk factors for colon cancer development as supported by epidemiological studies as well as controlled experimental animal studies. Our recent studies have shown that diet-induced obesity increases inflammatory protein production and cancer gene expression in the colon, which are directly related to the colon cancer risk. However, the mechanistic connection between inflammatory protein production and cancer gene expression remains to be determined. In this study, we demonstrate that the tumor necrosis factor-alpha, an inflammatory protein, causes the overexpression of cancer genes. This is a newly characterized molecular pathway underlying the diet-induced obesity and cancer. Our data provide novel insights into obesity-related cancer risk, and the information will be useful for scientists who are interested in the prevention of obesity-related colon cancer.
Technical Abstract: Obesity is an established risk factor for colorectal cancer, but the mechanism(s) responsible for this relationship are not adequately delineated. Our prior study showed that diet-induced obesity raised colonic tumor necrosis factor alpha (TNF-') concentrations, accompanied by pro-tumorigenic alterations in several components of the Wnt-signaling cascade. To test the hypothesis that there is a causal role of TNF-a in mediating this phenomenon, a TNF-a knockout mouse model was utilized in the present study. A 2 × 2 factorial study was performed, with wildtype and TNF-'-/- mice fed with a 60 kcal% high fat (HF) diet or a 10 kcal% low fat diet. TNF-'-/- mice did develop diet-induced obesity (p < 0.05), although the magnitude was attenuated by the ablation of TNF-' when compared to wildtype mice. Compared to female mice, wildtype male mice were more sensitive to the obesity-induced increase in colonic TNF-' (p < 0.05). Genetic ablation of TNF-' suppressed the obesity-promoted elevation of Wnt-signaling, as indicated by decreased levels of phospho-GSK3' and active '-catenin, two key components within the Wnt pathway (p < 0.05). The transcriptional expression of several Wnt-signaling targets (C-myc, Cyclin D1 and Axin 2) and cell proliferation, as indicated by Ki-67 staining, were attenuated by the deletion of TNF-' in an obese condition (p < 0.05). These data indicated that genetic deletion of TNF-' attenuated the tumorigenic Wnt-signaling, which was otherwise elevated by HF diet-induced obesity. In conclusion, our data clearly demonstrate a causal role of TNF-' in mediating obesity-associated Wnt-signaling and characterize an inflammatory mechanism for obesity-associated colorectal carcinogenesis.