Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Bevier Hall Room 472, Urbana, IL 61801, USA.
Br J Nutr. 2013 Jan 14;109(1):33-42. doi: 10.1017/S0007114512000876. Epub 2012 Apr 3.
The present study aimed to explore the role(s) of the soya isoflavone genistein (GEN) in preventing the development of colon pre-neoplasia, using Wingless/int (WNT)/β-catenin as a molecular marker of colon abnormality. Specifically, the effects on the WNT/β-catenin signalling pathway from GEN were examined by using an azoxymethane (AOM)-induced rat colon cancer model. Male Sprague-Dawley rats were fed a control (CTL), a soya protein isolate (SPI) or a GEN diet from gestation to 13 weeks of age. The first sampling was conducted at 7 weeks of age for pre-AOM analysis. The remaining rats were injected with AOM at 7 weeks of age. The descending colon was collected 6 weeks later for the evaluation of aberrant crypt foci (ACF), gene expression and nuclear protein accumulation. AOM injection induced aberrant nuclear accumulation of β-catenin in the CTL group but not in the SPI or GEN group. Moreover, the WNT target genes Cyclin D1 and c-Myc were repressed by SPI and GEN. Meanwhile, SPI and GEN suppressed the expression of WNT signalling genes including Wnt5a, Sfrp1, Sfrp2 and Sfrp5 to the similar level to that of the pre-AOM period. Rats fed SPI and GEN had a decreased number of total aberrant crypts. GEN feeding also resulted in a reduced number of ACF with N = 3 per foci. The reduction of WNT/β-catenin signalling was correlated with the decrease in total aberrant crypts. By testing WNT/β-catenin signalling as a biomarker of colon carcinogenic potential, we showed the novel role of GEN as a suppressor of carcinogen-induced WNT/β-catenin signalling in preventing the development of early colon neoplasia.
本研究旨在探讨大豆异黄酮金雀异黄素（GEN）在预防结肠癌前病变发展中的作用，将 Wnt/β-catenin 作为结肠癌异常的分子标志物。具体而言，使用氧化偶氮甲烷（AOM）诱导的大鼠结肠癌模型，研究 GEN 对 WNT/β-catenin 信号通路的影响。雄性 Sprague-Dawley 大鼠从妊娠到 13 周龄时分别喂食对照（CTL）、大豆蛋白分离物（SPI）或 GEN 饮食。第一次采样在 7 周龄进行，用于预 AOM 分析。其余大鼠在 7 周龄时注射 AOM。6 周后收集降结肠，评估异常隐窝病灶（ACF）、基因表达和核蛋白积累。AOM 注射诱导 CTL 组β-catenin 异常核积累，但 SPI 和 GEN 组没有。此外，SPI 和 GEN 抑制了 WNT 靶基因 Cyclin D1 和 c-Myc 的表达。同时，SPI 和 GEN 抑制了 WNT 信号基因的表达，包括 Wnt5a、Sfrp1、Sfrp2 和 Sfrp5，使其表达水平与预 AOM 期相似。喂食 SPI 和 GEN 的大鼠总异常隐窝数减少。GEN 喂养还导致 ACF 数量减少，每个焦点有 N=3 个。WNT/β-catenin 信号的减少与总异常隐窝的减少相关。通过测试 WNT/β-catenin 信号作为结肠癌致癌潜力的生物标志物，我们显示了 GEN 作为致癌物诱导的 WNT/β-catenin 信号抑制剂的新作用，可预防早期结肠癌前病变的发展。
