Suzuki Rikako, Kohno Hiroyuki, Suzui Masumi, Yoshimi Naoki, Tsuda Hiroyuki, Wakabayashi Keiji, Tanaka Takuji
Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan.
Carcinogenesis. 2006 Mar;27(3):619-30. doi: 10.1093/carcin/bgi241. Epub 2005 Oct 11.
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.
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致癌过程。为此，我们尝试使用携带人类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。将4-NQO（20 ppm）添加到Tg和非Tg大鼠的饮用水中，持续8周，然后在22周的实验期内比较舌癌发生情况。此外，我们测定了舌部病变的DNA倍体，并检测了细胞周期蛋白D1、谷胱甘肽S-转移酶胎盘型、环氧化酶（COX）-2、诱导型一氧化氮合酶（iNOS）和β-连环蛋白这五种生物标志物的免疫组化表达。接下来，在经4-NQO处理的Tg大鼠中检测了尼美舒利、吡格列酮和一种合成的香叶基化衍生物的癌症化学预防作用，据报道这些物质是舌癌发生的抑制剂。在饮用水中用4-NQO处理期间或之后，在Tg和非Tg大鼠的舌部均观察到舌发育异常和肿瘤，Tg大鼠的发生率和多发性更高。组织病理学检查显示，舌部存在鳞状细胞发育异常、乳头状瘤和有或无浸润的癌。免疫组化显示，随着疾病进展，针对五种生物标志物的表达水平升高，且这些变化与DNA倍体模式的变化相关。有趣的是，在鳞状细胞癌的浸润前沿观察到COX-2、iNOS和β-连环蛋白的强表达。随后使用Tg大鼠进行的化学预防研究表明，所测试的化学物质在4-NQO暴露后给药时可抑制舌癌的发生。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，可用于口腔癌发展的分析，同时也有助于识别针对口腔癌的潜在有效癌症化学预防剂。
