An animal model for the rapid induction of tongue neoplasms in human c-Ha-ras proto-oncogene transgenic rats by 4-nitroquinoline 1-oxide:: its potential use for preclinical chemoprevention studies
An animal model for the rapid induction of tongue neoplasms in human c-Ha-ras proto-oncogene transgenic rats by 4-nitroquinoline 1-oxide:: its potential use for preclinical chemoprevention studies
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DOI：
10.1093/carcin/bgi241
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发表时间：
2006-03-01
期刊：
影响因子：
4.7
通讯作者：
Tanaka, T
中科院分区：
文献类型：
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作者：
Suzuki, R;Kohno, H;Tanaka, T
口腔鳞状细胞癌是人类最常见的肿瘤之一，预防这种恶性肿瘤需要更好地了解其癌变过程。为此，我们尝试使用携带人c-Ha-ras原癌基因的转基因（Tg）大鼠和致癌物4-硝基喹啉1-氧化物（4-NQO）建立动物模型。4-NQO（20 p.m.）在Tg和非Tg大鼠的饮用水中给药8周，然后在22周的实验期间比较舌癌发生。此外，我们还测定了舌病变的DNA倍体，并检测了5种生物标志物的免疫组化表达，如细胞周期蛋白D1、胎盘型谷胱甘肽S-转移酶、环氧合酶（考克斯）-2、诱导型一氧化氮合酶（iNOS）和β-连环蛋白。接下来，在用4-NQO处理的Tg大鼠中检查尼美舒利、吡格列酮和合成的香叶基化衍生物的癌症化学预防作用，所述衍生物已被报道为舌癌发生的抑制剂。在饮用水中的4-NQO处理期间或之后，在Tg和非Tg大鼠的舌上观察到舌发育不良和肿瘤，其中在Tg大鼠中具有更大的发生率和多样性。组织学检查可见舌鳞状细胞不典型增生、乳头状瘤和癌伴或不伴浸润。免疫组化显示，针对五种生物标志物的表达水平随着疾病进展而增加，并且这些变化与DNA倍体模式的变化相关。有趣的是，考克斯-2、iNOS和β-连环蛋白在鳞状细胞癌的浸润前沿观察到强表达。随后使用Tg大鼠进行的化学预防研究表明，在接触4-NQO后给予测试的化学品可抑制舌癌的发生。因此，这些结果可能表明，我们的4-NQO诱导的Tg大鼠舌癌发生模型模拟了人类口腔癌发生的许多方面，它可以应用于口腔癌的发展分析，同时也有助于确定潜在的有效的癌症化学预防剂对口腔癌。
Oral squamous cell carcinoma is one of the most common human neoplasms, and prevention of this malignancy requires a better understanding of its carcinogenesis process. To this end, we tried to establish an animal model using the human c-Ha-ras proto-oncogene-carrying transgenic (Tg) rats and the carcinogen 4-nitroquinoline 1-oxide (4-NQO). 4-NQO (20 p.p.m.) was administered to Tg and non-Tg rats for 8 weeks in their drinking water, and then the occurrence of tongue carcinogenesis was compared during the experimental period of 22 weeks. In addition, we determined the DNA ploidy in tongue lesions and examined the immunohistochemical expression of five biomarkers such as cyclin D1, glutathione S-transferase placental form, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and beta-catenin. Next, the cancer chemopreventive effects of nimesulide, pioglitazone and a synthetic geranylated derivative, which have been reported to be inhibitors of tongue carcinogenesis, were examined in Tg rats treated with 4-NQO. Either during or after treatment with 4-NQO in the drinking water, tongue dysplasia and tumors were observed on the tongues of both Tg and non-Tg rats, with a greater incidence and multiplicity in Tg rats. Histopathologically, squamous cell dysplasia, papilloma and carcinoma with or without invasion were present in the tongue. Immunohistochemistry revealed that expression levels against five biomarkers increase with disease progression, and the changes correlated with those of the DNA ploidy pattern. Interestingly, a strong expression of COX-2, iNOS and beta-catenin was observed on the invasive front of squamous cell carcinomas. A subsequent chemoprevention study using Tg rats showed that the chemicals tested suppressed the occurrence of tongue carcinomas when they were administered after 4-NQO-exposure. These results may thus indicate that our 4-NQO-induced Tg rat tongue carcinogenesis model simulates many aspects of human oral carcinogenesis and it can be applied for an analysis of oral cancer development while also helping to identify potentially effective cancer chemopreventive agents against oral cancer.