Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer.
Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer.
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DOI：
10.1016/j.jnutbio.2011.07.002
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Mason JB
中科院分区：
文献类型：
--
作者：
Liu Z;Brooks RS;Ciappio ED;Kim SJ;Crott JW;Bennett G;Greenberg AS;Mason JB
与肥胖相关的炎症可能在结直肠癌发生中起作用，但其潜在机制尚不清楚。本研究探讨了Wnt通路（在结直肠癌发生中起关键作用的细胞内信号级联）是否被肥胖诱导的炎症细胞因子肿瘤坏死因子-α (TNF-α)升高激活。动物实验采用C57BL/6小鼠，采用高脂饮食（60% kcal）诱导肥胖。进行炎症特异性微阵列检测，并用实时聚合酶链反应证实结果。结果显示，饮食性肥胖使结肠中TNF-α的表达增加72% (P= 0.004)，白细胞介素-18的表达增加41% （P= 0.023）。离体培养法测定肥胖动物的结肠TNF-α蛋白浓度几乎增加了一倍（P= 0.002）。糖原合成酶激酶3β (GSK3β)是Wnt信号的重要中间抑制剂，也是TNF-α的潜在靶点，我们用免疫组织化学方法定量了GSK3β的磷酸化。GSK3β的失活（磷酸化）形式在肥胖小鼠结肠黏膜中升高（P< 0.02）。此外，典型Wnt信号的关键效应因子β-catenin在肥胖小鼠的结肠中升高（P< 0.05），下游靶基因c-myc的表达也升高（P< 0.05）。这些数据表明，饮食诱导的肥胖会导致结肠TNF-α升高，并引发Wnt信号通路中一些关键成分的改变，这些改变在本质上是促进转化的。因此，这些观察结果为一种生物学上合理的途径提供了证据，即肥胖增加结直肠癌风险的Wnt途径。
Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF-α in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-α protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3β), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-α, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3β was elevated in the colonic mucosa of obese mice (P<.02). Moreover, β-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF-α and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer.
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作者：
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影响因子：
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