Knockout mice reveal a tumor suppressor function for Testin
Knockout mice reveal a tumor suppressor function for Testin
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DOI：
10.1073/pnas.0504934102
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发表时间：
2005-08-02
影响因子：
11.1
通讯作者：
Croce, CM
中科院分区：
文献类型：
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作者：
Drusco, A;Zanesi, N;Croce, CM
Testin（TES）基因先前被鉴定为位于7q31.2的推定的人类肿瘤抑制基因，7q31.2是在造血系统恶性肿瘤以及上皮肿瘤中经常缺失的区域。为了确定TES是否在体内作为肿瘤抑制因子，我们产生了Tes基因敲除小鼠，然后将其用于致癌物诱导的胃癌的建立模型中。在小鼠中，缺锌（ZD）饮食增强了前胃细胞增殖和对N-亚硝基甲基苄胺（NMBA）诱导的致癌作用的敏感性。将5周龄的Tes野生型（+/+）、杂合型（+/-）和纯合型（-/-）小鼠分为4组：饲喂锌充足饮食（ZS）的小鼠;饲喂ZD饮食的小鼠;饲喂ZS + NMBA处理的小鼠（ZS+NMBA）和饲喂ZD + NMBA处理的小鼠（ZD+NMBA）。4周后，ZS+NMBA组和ZD+NMBA组分别灌胃3个剂量的NMBA。NMBA给药后8周处死动物：25%的+/+小鼠出现良性病变; 88%的+/-小鼠显示多发性乳头状瘤、非典型腺化生和鳞状细胞癌; 81%的-/-小鼠显示非常大的乳头状瘤、鳞状细胞癌和腺癌。肿瘤发生率在+/-与+/+之间和-/-与+/+之间存在统计学显著差异（P < 0.0001）。这些数据表明，Tes功能作为一个肿瘤抑制基因在体内。
The Testin (TES) gene was previously identified as a putative human tumor suppressor gene at 7q31.2, a region that is frequently deleted in hematopoietic malignancies, as well as in epithelial tumors. To determine whether TES acts as a tumor suppressor in vivo, we generated a Tes knockout mouse and then used it in an established model of carcinogen-induced gastric cancer. In mice a zinc-deficient (ZD) diet enhances cellular proliferation in the forestomach and susceptibility to N-nitrosomethyl-benzylamine (NMBA)-induced carcinogenesis. Five-week-old Tes wild-type (+/+), heterozygous (+/-), and homozygous (-/-) mice were divided into four groups: mice fed a zinc-sufficient diet (ZS); mice fed a ZD diet; ZS fed plus NMBA-treated mice (ZS+NMBA), and ZD fed plus NMBA-treated mice (ZD+NMBA). After 4 weeks, the ZS+NMBA and ZD+NMBA groups were treated with three intragastric doses of NMBA. Animals were killed 8 weeks after NMBA administration: 25% of +/+ mice developed benign lesions; 88% of +/- showed multiple papillomas, atypical glandular metaplasia, and squamous cell carcinomasl; and 81% of -/- mice displayed very large papillomas, squamous cell carcinomas, and adenocarcinomas. A statistically significant difference in tumor incidence was found between +/- versus +/+ and -/- versus +/+ (P < 0.0001). These data suggest that Tes functions as a tumor suppressor gene in vivo.