beta-Catenin/NF-kappaBeta and Colon Cancer

描述(由申请人提供)： 增殖率的增加是正常结肠上皮向癌症转化的最早的，也是最有可能的必要背景。慢性肠炎，尤其是结肠炎症，也会显著增加罹患癌症的风险。然而，炎症、增殖和肿瘤发生之间复杂的相互关系还不是很清楚。我们采用了一种小鼠模型(TMCH)来研究促炎细胞因子和饮食丁酸如何调节核因子B(NF-kappaB)和β-catenin介导的天然结肠粘膜细胞计数的增加。TMCH以上皮细胞过度增殖和增殖为特征。根据遗传背景的不同，会发生不同程度的炎症，其病理生理与人类炎症性胃肠道疾病相似。在近交系小鼠中，TMCH的发生之前有一过性的肿瘤坏死因子-α和干扰素-γ的增加，以及粘膜β-连环素丰度、磷酸化和下游靶标(细胞周期蛋白DL，c-myc)信号的平行有丝分裂变化。随着肿瘤坏死因子-α的表达，核转录因子-kappaB活性/核转位的变化。饮食中的果胶(丁酸的来源)可消除TMCH中的增生反应。在遗传易感的C3H/HeNHsd(C3H)近交系小鼠中，可在整个结肠内看到与上皮内CD3+/CD103+T细胞显著增加相关的慢性炎症。基于这些发现，我们的目标是：1.确定肿瘤坏死因子-α和丁酸盐如何调节非炎症结肠粘膜中β-连环蛋白/核因子-kappaB的表达/活性、亚细胞分布和信号；2.确定在慢性炎症过程中，肿瘤坏死因子-α和丁酸盐如何调节β-连环蛋白/核因子-kappaB的表达/活性、亚细胞分布和信号转导。为了实现这些目标，我们打算利用体内中和肿瘤坏死因子-α抗体，并直接将结肠粘膜暴露于优达格利特包被的丁酸钠微丸。这些研究将帮助我们描述肿瘤坏死因子-α和丁酸盐如何分别调节β-连环蛋白/核因子-kappaB介导的过度增殖/炎症和随后的粘膜启动致癌。通过研究核因子-kappaB和β-连环素介导的细胞普查增加的机制基础，在没有和存在慢性炎症的情况下，我们可能会发现降低癌症风险的新的治疗策略。

DESCRIPTION (provided by applicant): Increased rates of proliferation form the earliest and, most probably, the necessary background for the transformation of a normal colonic epithelium to cancer. Chronic intestinal inflammation, especially of the colon, also significantly increases risk of developing cancer. However, the complex inter-relationships among inflammation, proliferation and neoplasia generation, is less well understood. We have employed a mouse model (Transmissible Murine Colonic Hyperplasia, TMCH) to study how pro-inflammatory cytokines and dietary butyrate regulate nuclear factor-(B (NF-kappaB) and beta-catenin mediated increases in cell census in the native colonic mucosa. TMCH is characterized by epithelial hyperproliferation and hyperplasia. Depending upon the genetic background, varying degrees of inflammation occur with pathophysiological similarities to human inflammatory gastrointestinal diseases. In outbred mice, onset of TMCH was preceded by transient increases in TNF-alpha and IFN-gamma, and parallel mitogenic changes in mucosal beta-catenin abundance, phosphorylation and downstream targets (cyclin Dl, c-myc) signaling. Changes in NF-kappaB activity /nuclear translocation followed TNF-alpha expression. Dietary pectin (source of butyrate) abrogated the hyperplastic responses during TMCH. In genetically susceptible C3H/HeNHsd (C3H) inbred mice, a chronic inflammation associated with dramatic increases in intra-epithelial CD3+/CD 103+ T cells, could be seen in the entire colon. Based on these findings, we aim to: 1. Determine how TNF-alpha and butyrate modulate beta-catenin/NF-kappaB expression/activity, sub-cellular distribution, and signaling in the non-inflamed colonic mucosa; 2. Determine how TNF-alpha and butyrate modulate beta-catenin/NF-kappaB expression/activity, subcellular distribution, and signaling during chronic inflammation. To accomplish these goals, we intend to utilize in vivo neutralizing TNF-alpha antibody and direct colonic mucosal exposure to Eudagrit coated sodium butyrate pellets. These studies will help us delineate how TNF-alpha and butyrate individually modulate beta-catenin/NF-kappaB mediated hyperproliferation /inflammation and subsequent mucosal priming for carcinogenesis. By studying a mechanistic basis of NF-kappaB and beta-catenin mediated increases in cell census, in the absence and presence of chronic inflammation, we may identify new treatment strategies for reducing cancer risk.