Li Qingjie, Löhr Christiane V, Dashwood Roderick H
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.
Cancer Lett. 2009 Sep 28;283(1):36-42. doi: 10.1016/j.canlet.2009.03.026. Epub 2009 Apr 18.
Activator protein 2alpha (AP-2alpha) is a putative tumor suppressor, and various reports have described the loss or reduction of AP-2alpha expression in cutaneous malignant melanomas, as well as in cancers of the prostate, breast and colon. Previously, AP-2alpha was shown to attenuate beta-catenin/T-cell factor-4 (TCF-4) nuclear interactions and beta-catenin/TCF-4-dependent transcriptional activity in human colorectal cancer cells [Q. Li, R.H. Dashwood, Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells, J. Biol. Chem. 279 (2004) 45669-45675]. Here, we show that in vivo gene delivery of AP-2alpha suppressed intestinal polyp formation in the Apc(min) mouse, and protected against the development of anemia and splenomegaly. Immunoblot analyses and immunohistochemistry following gene delivery revealed an increase in AP-2alpha expression in the mouse intestinal mucosa and liver. Co-immunoprecipitation experiments provided evidence for interactions between AP-2alpha, beta-catenin, and adenomatous polyposis coli (APC) proteins in mouse intestinal mucosa, as well as in a primary human colorectal cancer. Collectively, these studies support a tumor suppressor role for AP-2alpha in the gastrointestinal tract, and suggest that AP-2alpha represents a novel target for therapeutic intervention in human cancers characterized by dysregulated Wnt signaling.
激活蛋白2α（AP - 2α）被认为是一种肿瘤抑制因子，多项报道称在皮肤恶性黑色素瘤以及前列腺癌、乳腺癌和结肠癌中存在AP - 2α表达缺失或降低的情况。此前研究表明，在人结肠癌细胞中，AP - 2α可减弱β - 连环蛋白/T细胞因子4（TCF - 4）的核内相互作用以及β - 连环蛋白/TCF - 4依赖的转录活性[Q. Li, R.H. Dashwood, 《激活蛋白2α与腺瘤性息肉病大肠杆菌/β - 连环蛋白结合并抑制结肠癌细胞中β - 连环蛋白/T细胞因子的转录活性》，《生物化学杂志》279 (2004) 45669 - 45675]。在此，我们发现，在体内将AP - 2α基因导入Apc(min)小鼠可抑制肠道息肉形成，并预防贫血和脾肿大的发生。基因导入后的免疫印迹分析和免疫组织化学显示，小鼠肠黏膜和肝脏中AP - 2α表达增加。免疫共沉淀实验为AP - 2α、β - 连环蛋白和腺瘤性息肉病大肠杆菌（APC）蛋白在小鼠肠黏膜以及原发性人结肠癌中的相互作用提供了证据。总体而言，这些研究支持AP - 2α在胃肠道中具有肿瘤抑制作用，并表明AP - 2α是针对以Wnt信号失调为特征的人类癌症进行治疗干预的新靶点。
