Oncotarget, 2016, 7(14):17870-17884.

Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2-β-catenin axis

Qianming Du, Yajing Wang, Chao Liu, et al

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing, P.R. China; et al

Nonresolving inflammation in the intestine predisposes individuals to colitis-associated colorectal cancer (CAC), which leads to high morbidity and mortality. Here we show that genistein-27 (GEN-27), a derivative of genistein, inhibited proliferation of human colorectal cancer cells through inhibiting β-catenin activity. Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced β-catenin nuclear localization, which resulted from the inhibition of NF-κB/p65 nuclear localization and up-regulation of caudal-related homeobox transcription factor 2 (CDX2). Furthermore, GEN-27 decreased binding of p65 to the silencer region of CDX2 and increased binding of CDX2 to the promoter regions of APC and AXIN2, thus inhibiting the activation of β-catenin induced by TNF-α. Importantly, GEN-27 protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and tumor volume. Histopathology, immunohistochemistry and flow cytometry revealed that dietary GEN-27 significantly decreased secretion of proinflammatory cytokines and macrophage infiltration. Moreover, GEN-27 inhibited AOM/DSS-induced p65 and β-catenin nuclear translocation, while promoted the expression of CDX2, APC, and AXIN2. Taken together, our findings demonstrate that the anti-proliferation effect of GEN-27 in vitro and the prevention of CAC in vivo is mediated by p65-CDX2-β-catenin axis via inhibiting β-catenin target genes. Our results imply that GEN-27 could be a promising candidate for the chemoprevention of CAC.

美国《Oncotarget》杂志， 2016, 7(14):17870-17884.

GEN-27（一种染料木黄酮衍生物）在结肠癌中的化学预防活性由p65-CDX2-β-连环蛋白轴介导

杜前明，王亚静，刘超等

中国药科大学生理学系天然药物国家重点实验室，江苏，南京，中国; 等

在肠道中的非分辨性炎症使个体易患结肠炎相关的结肠直肠癌（CAC），这导致高的发病率和死亡率。在这里我们显示染料木素-27（GEN-27），染料木素的衍生物，通过抑制β-连环蛋白活性抑制人类结肠直肠癌细胞的增殖。我们的研究结果表明，GEN-27增加腺瘤性息肉病大肠杆菌（APC）和轴抑制蛋白2（AXIN2）的表达，减少β-连环蛋白核定位，这是由抑制NF-κB/ p65核定位和上调导致的的尾部相关同源盒转录因子2（CDX2）。此外，GEN-27降低p65与CDX2的沉默子区域的结合，增加CDX2与APC和AXIN2的启动子区域的结合，从而抑制由TNF-α诱导的β-联蛋白的活化。重要的是，GEN-27保护小鼠免受氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的结肠癌变，具有降低的死亡率，肿瘤数量和肿瘤体积的作用。组织病理学，免疫组织化学和流式细胞术显示饮食GEN-27显着减少促炎细胞因子和巨噬细胞浸润的分泌。此外，GEN-27抑制AOM / DSS诱导的p65和β-连环蛋白核易位，同时促进CDX2，APC和AXIN2的表达。总之，我们的研究结果表明GEN-27在体外的抗增殖作用和体内CAC的预防由p65-CDX2-β-联蛋白轴通过抑制β-联蛋白靶基因介导。我们的结果表明GEN-27可能是化学预防CAC的有前途的药物。