The influence of genetic ablation of tumor necrosis factor‐α on the colonic Wnt pathway cascade under an obese state

Abstract

Obesity is an established risk factor for colorectal cancer (CRC), but the mechanism(s) responsible for this relationship are still not fully understood. We hypothesize that obesity creates a low‐grade colonic inflammatory microenvironment, which facilitates the development of CRC. Our prior study suggested tumor necrosis factor alpha (TNF‐α) might elevate the Wnt‐signaling, and thereby promote the colonic tumorigenesis. In the present study, we observed that several colonic inflammatory cytokines (TNF‐α, IL‐1β, IFNg) and Wnt pathway specific genes (e.g. Axin2) were upregulated in an obese state (p < 0.05), whereas the genetic ablation of TNF‐α suppressed the elevation of Wnt‐signaling induced by dietary obesity, as indicated by decreased levels of phopho‐GSK3β, and active β‐Catenin (p < 0.05), two key components in Wnt pathway cascade. A Wnt pathway specific gene expression profiling further demonstrated that the genetic abolishment of TNF‐α attenuated aberrations of several genes within the colonic Wnt pathway cascade including the over‐expressed Axin2, a readout of the Wnt pathway (p < 0.05). Colonic epithelial proliferation (Ki‐67), which is partially under the control of Wnt signaling, was also decreased by the blockade of TNF‐in obese mice (p < 0.05). These results indicate that obesity‐driven inflammation plays a role in the regulation of the tumorigenic Wnt‐signaling pathway, which contributes to the development of obesity‐associated CRC.Support or Funding InformationSupported in part by a USDA/NIFA grant, a USDA/Hatch grant and a HNRCA competitive intramural pilot grant to ZL