Enhanced colitis-associated colon carcinogenesis in a novel Apc mutant rat
Enhanced colitis-associated colon carcinogenesis in a novel Apc mutant rat
复制标题
DOI：
10.1111/j.1349-7006.2009.01287.x
复制
发表时间：
2009-11-01
期刊：
影响因子：
5.7
通讯作者：
Kuramoto, Takashi
中科院分区：
文献类型：
--
作者：
Yoshimi, Kazuto;Tanaka, Takuji;Kuramoto, Takashi
为了建立一种有效的结肠炎相关性结直肠癌大鼠模型，将氧化偶氮甲烷和葡聚糖硫酸钠（AOM/DSS）诱导的结肠癌发生应用于一种新的腺瘤性息肉病结肠（APC）突变体，京都APC Delta（KAD）大鼠。KAD大鼠来源于乙基亚硝基脲诱变，并在Apc基因（S2523 X）中携带无义突变。KAD大鼠的截短APC被推断为缺乏部分基本结构域、EB 1结合结构域和PDZ结构域，但保留了完整的β-连环蛋白结合区。在F344大鼠遗传背景上Apc突变纯合子的KAD大鼠在胃肠道中未显示自发性肿瘤。在5周龄时，对雄性KAD大鼠单次皮下给予AOM（20 mg/kg，体重）。一周后，他们接受了为期一周的DSS（饮用水中2%）。在第15周，与F344大鼠相比，KAD大鼠中结肠肿瘤的发生率和多重性显著严重：发生率为100 vs 50%，多重性为10.7 +/- 3.5 vs 0.8 +/- 1.0。KAD肿瘤主要分布在直肠和远端结肠，类似于人类结直肠癌。β-catenin蛋白的积累和频繁的β-catenin突变是KAD结肠肿瘤的突出特征。据我们所知，使用KAD大鼠的AOM/DSS诱导的结肠癌发生是在大鼠中诱导结肠肿瘤的最有效的，因此可用作人结肠炎相关CRC的良好模型。（Cancer Sci 2009）。
To establish an efficient rat model for colitis-associated colorectal cancer, azoxymethane and dextran sodium sulfate (AOM/DSS)-induced colon carcinogenesis was applied to a novel adenomatous polyposis coli (Apc) mutant, the Kyoto Apc Delta (KAD) rat. The KAD rat was derived from ethylnitrosourea mutagenesis and harbors a nonsense mutation in the Apc gene (S2523X). The truncated APC of the KAD rat was deduced to lack part of the basic domain, an EB1-binding domain, and a PDZ domain, but retained an intact beta-catenin binding region. KAD rats, homozygous for the Apc mutation on a genetic background of the F344 rat, showed no spontaneous tumors in the gastrointestinal tract. At 5 weeks of age, male KAD rats were given a single subcutaneous administration of AOM (20 mg/kg, bodyweight). One week later, they were given DSS (2% in drinking water) for 1 week. At week 15, the incidence and multiplicity of colon tumors developed in the KAD rat were remarkably severe compared with those in the F344 rat: 100 versus 50% in incidence and 10.7 +/- 3.5 versus 0.8 +/- 1.0 in multiplicity. KAD tumors were dominantly distributed in the rectum and distal colon, resembling human colorectal cancer. Accumulation of beta-catenin protein and frequent beta-catenin mutations were prominent features of KAD colon tumors. To our knowledge, AOM/DSS-induced colon carcinogenesis using the KAD rat is the most efficient to induce colon tumors in the rat, and therefore would be available as an excellent model for human colitis-associated CRC.(Cancer Sci 2009).