Møllersen Linda, Paulsen Jan Erik, Olstørn Hege Benedikte, Knutsen Helle Katrine, Alexander Jan
Department of Food Toxicology, Norwegian Institute of Public Health, Oslo, Norway.
Carcinogenesis. 2004 Jan;25(1):149-53. doi: 10.1093/carcin/bgg176. Epub 2003 Sep 26.
Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of beta-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/beta-catenin signalling. Recently it was reported that beta-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing beta-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3-6 after birth and then treated with 50 mg/kg dietary RA in 1-3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in beta-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.
视黄酸（RA）的化学预防活性先前已在大鼠结肠中得到证实。Min/+小鼠携带肿瘤抑制基因腺瘤性息肉病 coli（Apc）的种系突变，其自发肿瘤发生的特征是Apc失活、β-连环蛋白的核积累以及由T细胞因子（TCF）/β-连环蛋白信号激活的特定基因的表达增强。最近有报道称，β-连环蛋白以视黄酸依赖的方式与视黄酸受体相互作用，减少β-连环蛋白/TCF调节的转录。因此，我们的假设是，全反式视黄酸的膳食补充可能会抑制Min/+小鼠中Apc驱动的肿瘤发生。令人惊讶的是，在两个不同的实验中，结果表明膳食视黄酸显著刺激了小肠肿瘤的形成和生长。在第一个实验中，Min/+小鼠在出生后第3至6天暴露于50毫克2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶/千克体重，然后从2周龄开始在1至3周内用50毫克/千克的膳食视黄酸处理。在第二个实验中，小鼠未用致癌物处理，并且从4周龄开始直到11周实验结束，饮食中补充5或10毫克/千克的视黄酸。免疫组织化学研究显示，视黄酸处理后β-连环蛋白、细胞周期蛋白D1或增殖细胞核抗原染色没有差异。喂食10毫克/千克视黄酸的小鼠没有肠道毒性，这表明Min/+小鼠中肿瘤发生增加是全反式视黄酸的特异性作用。
