Yamashita Satoshi, Wakazono Kuniko, Sugimura Takashi, Ushijima Toshikazu
Carcinogenesis Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Carcinogenesis. 2002 Jun;23(6):923-8. doi: 10.1093/carcin/23.6.923.
Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/NJcl (ACI) rats show persistent and strong cell proliferation in response to gastric mucosal damage by MNNG while BUF/NacJcl (BUF) rats show transient and limited cell proliferation. This difference is considered as one of the mechanisms for the high susceptibility of ACI rats to MNNG-induced stomach carcinogenesis. To identify genes involved in the differential induction of cell proliferation, cDNA subtraction was performed using RNA isolated from the pylorus of ACI and BUF rats treated with MNNG. By the temporal patterns of their expressions, the isolated 16 genes were overviewed and clustered into groups. Expression of the genes in group 1 (such as MHC class I and class II genes and interferon-inducible genes Iigp, Mx2 and Ubd) was induced by MNNG treatment, and the genes in group 2 (such as cellular retinoic acid-binding protein II (CrabpII)) were constantly expressed regardless of MNNG treatment. Then, expression profiles among multiple rat strains were compared with the extents of induction of cell proliferation. Iigp, CrabpII and EST222005 were found to show relatively good accordance, and these three genes were considered as candidates for genes that control differential induction of cell proliferation. Presence of polymorphisms at the genomic DNA level was indicated for CrabpII and EST222005, and these two genes were considered to be better candidates than IIGP: It was shown that the temporal profiles and profiles among strains, taking advantage of animal models, are useful to select candidate genes from a collection of genes isolated by various genome-wide scanning methods.
N-甲基-N'-硝基-N-亚硝基胍（MNNG）诱导的大鼠胃癌被广泛用作分化型人类胃癌的模型。ACI/NJcl（ACI）大鼠在受到MNNG引起的胃黏膜损伤时会表现出持续且强烈的细胞增殖，而BUF/NacJcl（BUF）大鼠则表现出短暂且有限的细胞增殖。这种差异被认为是ACI大鼠对MNNG诱导的胃癌发生高度易感性的机制之一。为了鉴定参与细胞增殖差异诱导的基因，使用从经MNNG处理的ACI和BUF大鼠幽门分离的RNA进行了cDNA消减。根据基因表达的时间模式，对分离出的16个基因进行了概述并分组。第1组基因（如MHC I类和II类基因以及干扰素诱导基因Iigp、Mx2和Ubd）的表达在MNNG处理后被诱导，而第2组基因（如细胞视黄酸结合蛋白II（CrabpII））无论是否进行MNNG处理都持续表达。然后，将多个大鼠品系之间的表达谱与细胞增殖的诱导程度进行了比较。发现Iigp、CrabpII和EST222005表现出相对较好的一致性，这三个基因被认为是控制细胞增殖差异诱导的候选基因。CrabpII和EST222005在基因组DNA水平上存在多态性，这两个基因被认为比IIGP更适合作为候选基因：利用动物模型的时间谱和品系间谱，从通过各种全基因组扫描方法分离的基因集合中选择候选基因是有用的。
