Obesity is an established risk factor for colorectal cancer, but the mechanisms responsible for this relationship are not adequately delineated. Using a TNF-α^−/− mouse model, the present study aimed to test the causal role of TNF-α in mediating the promotion of tumorigenic Wnt signaling by high-fat diet-induced obesity. A 2×2 factorial study was performed with wild-type and TNF-α^−/− 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-α^−/− animals (P<.05), but males were more sensitive to high-fat diet-induced weight gain and increases of colonic TNF-α than females (P<.05). Genetic ablation of TNF-α suppressed the obesity-promoted elevation of Wnt signaling, as indicated by decreased levels of phospho-GSK3β and active β-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-α in the high-fat-fed TNF-α^−/− animals comparing with the wild-type animals (P<.05). Our data collectively showed that the genetic deletion of TNF-α attenuated the tumorigenic Wnt signaling, which was otherwise elevated by high-fat diet-induced obesity, and demonstrated a causal role of TNF-α in mediating obesity-associated Wnt signaling, which indicates a potential mechanism of inflammation-driven Wnt signaling for obesity-associated colorectal carcinogenesis.

肥胖是结直肠癌的既定危险因素，但尚未充分阐明造成这种关系的机制。本研究使用TNF-α ^-/-小鼠模型，旨在测试TNF-α在介导高脂饮食诱导的肥胖促进致瘤性Wnt信号传导中的因果作用。在60 kcal％高脂饮食或10 kcal％低脂饮食下，对野生型和TNF-α ^-/-小鼠进行了2×2析因研究。通过电化学发光测定，实时PCR，Western印迹或免疫组织化学测量Wnt信号通路内的炎性细胞因子概况和基因。高脂饮食会增加野生型和TNF-α ^-/-动物的体重（P <.05），但男性比女性对高脂饮食诱导的体重增加和结肠TNF-α的增加更敏感（P <.05）。TNF-α的基因消融抑制了肥胖促进的Wnt信号转导升高，这是由Wnt途径中的两个关键成分磷酸GSK3β和活性β-连环蛋白水平降低所表明的（P <.05）。高脂喂养的TNF-α的TNF-α的缺失减弱了一些Wnt信号靶的转录表达（C-myc，Cyclin D1和Axin 2）和细胞增殖，如Ki-67染色所示。^-/-动物与野生型动物比较（P <.05）。我们的数据共同表明，TNF-α的基因缺失减弱了致瘤性Wnt信号传导，否则高脂饮食诱导的肥胖会使其升高，并证明TNF-α在介导肥胖相关的Wnt信号传导中具有因果作用，这表明肥胖相关结直肠癌发生的炎症驱动Wnt信号转导的潜在机制。