Tumor necrosis factor-a knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice

Authors: LI, JINCHAO - University Of Massachusetts; TANG, YING - University Of Massachusetts; LIN, TING-CHUN - University Of Massachusetts; Zeng, Huawei; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LUI, ZHENHUA - University Of Massachusetts

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/14/2023
Publication Date: 4/20/2023
Citation: Li, J., Tang, Y., Lin, T., Zeng, H., Mason, J.B., Lui, Z. 2023. Tumor necrosis factor-a knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice. Journal of Nutritional Biochemistry. 117. Article 109355. https://doi.org/10.1016/j.jnutbio.2023.109355.
DOI: https://doi.org/10.1016/j.jnutbio.2023.109355

Interpretive Summary: Colon cancer is a major public health issue in the US, with approximately 150,000 new cases and 52,000 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 raised the level of colonic tumor necrosis factor alpha (TNF-a, an inflammatory cytokine), accompanied by pro-tumorigenic gene expression. However, the causal role of TNF-a in mediating the above observation remains to be determined. In this study, we demonstrate a causal role of TNF-a in mediating obesity-associated colorectal carcinogenesis. These data provide novel insights into obesity-related cancer risk and will be useful for scientists who are interested in the prevention of obesity-related colon cancer.

Technical Abstract: There is strong evidence from observational studies showing that having more body fat increases an individual's risk of developing colorectal cancer (CRC), but the causality between obesity and CRC remains inadequately elucidated. Our previous studies have shown diet-induced obesity is associated with elevated TNF-a and hyperactive Wnt-signaling, yet the causal role of TNF-a has not been precisely studied. The present study aims to examine the functionality of TNF-a in the development of CRC associated with obesity. We examined the extent to which diet-induced obesity elevates intestinal tumorigenesis by comparing Apc1638N mice fed a low-fat diet (LFD, 10 kcal% fat) with those fed a high fat diet (HFD, 60 kcal% fat), and then investigated the degree that genetic ablation of TNF-a attenuates the effect by crossing the TNF-a/- mice with Apc1638N mice and feeding them with the same HFD (TNF-a KO HFD). After 16-week feeding, the HFD significantly increased the intestinal tumorigenesis, whereas the deletion of TNF-a attenuated the effect (p < 0.05). Accompanying with the changes of macroscopic tumor, HFD significantly elevated intestinal inflammation and the tumorigenic Wnt-signaling, whereas the abolishment of TNF-a mitigated the magnitude of these elevations (p < 0.05). In summary, our findings demonstrated that the loss of TNF-a could attenuate obesity associated intestinal tumorigenesis via decreasing the intestinal inflammation and thereby the Wnt-signaling, indicating that TNF-a is potentially a significant target that can be utilized to reduce the risk of CRC associated with obesity, which has reached an epidemic level worldwide.