| First Author | Guo C | Year | 2020 |
| Journal | J Nutr Biochem | Volume | 77 |
| Pages | 108302 | PubMed ID | 31825818 |
| Mgi Jnum | J:303636 | Mgi Id | MGI:6690776 |
| Doi | 10.1016/j.jnutbio.2019.108302 | Citation | Guo C, et al. (2020) Genetic ablation of tumor necrosis factor-alpha attenuates the promoted colonic Wnt signaling in high fat diet-induced obese mice. J Nutr Biochem 77:108302 |
| abstractText | Obesity is an established risk factor for colorectal cancer, but the mechanisms responsible for this relationship are not adequately delineated. Using a TNF-alpha(-/-) mouse model, the present study aimed to test the causal role of TNF-alpha in mediating the promotion of tumorigenic Wnt signaling by high-fat diet-induced obesity. A 2x2 factorial study was performed with wild-type and TNF-alpha(-/-) mice on a 60 kcal% high-fat diet or a 10 kcal% low-fat diet. The inflammatory cytokine profile and genes within the Wnt signaling pathway were measured by electrochemiluminescence assay, real-time PCR, Western blotting or immunohistochemistry. The high-fat diet increased body weights in both wild-type and TNF-alpha(-/-) animals (P<.05), but males were more sensitive to high-fat diet-induced weight gain and increases of colonic TNF-alpha than females (P<.05). Genetic ablation of TNF-alpha suppressed the obesity-promoted elevation of Wnt signaling, as indicated by decreased levels of phospho-GSK3beta and active beta-catenin, two key components within the Wnt pathway (P<.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-alpha in the high-fat-fed TNF-alpha(-/-) animals comparing with the wild-type animals (P<.05). Our data collectively showed that the genetic deletion of TNF-alpha attenuated the tumorigenic Wnt signaling, which was otherwise elevated by high-fat diet-induced obesity, and demonstrated a causal role of TNF-alpha in mediating obesity-associated Wnt signaling, which indicates a potential mechanism of inflammation-driven Wnt signaling for obesity-associated colorectal carcinogenesis. |
