A novel rasH2 mouse carcinogenesis model that is highly susceptible to 4-NQO-induced tongue and esophageal carcinogenesis is useful for preclinical chemoprevention studies
A novel rasH2 mouse carcinogenesis model that is highly susceptible to 4-NQO-induced tongue and esophageal carcinogenesis is useful for preclinical chemoprevention studies
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DOI：
10.1093/carcin/bgm225
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发表时间：
2008-02-01
期刊：
影响因子：
4.7
通讯作者：
Tanaka, Takuji
中科院分区：
文献类型：
--
作者：
Miyamoto, Shingo;Yasui, Yumiko;Tanaka, Takuji
我们在雄性CB 6 F1-Tg-rasH 2 @Jcl小鼠（Tg小鼠）中研究了4-硝基喹啉1-氧化物（4-NQO）诱导的舌癌发生的易感性。对Tg小鼠施用4-NQO（在饮用水中20 p. p.m.）2、4、6或8周，并且此后它们不被处理直至第24周。在第24周，与用4-NQO处理2、4和6周的其他组（各20%的发生率）相比，在接受4-NQO 8周的小鼠中观察到更高的舌肿瘤伴异型增生的发生率（80%）。在Tg小鼠中也发生了食管肿瘤，为4-NQO。免疫组化观察显示，EP受体，尤其是EP 1和EP 2在4-NQO诱发的舌和食管病变中均有表达，提示前列腺素（PG）E-2和EP 1，2受体参与舌和食管癌的发生。使用该动物模型，我们研究了匹伐他汀（饮食中1，5和10 p. p.m.，持续15周）的潜在化学预防能力，从停止4-NQO暴露（饮用水中20 p. p.m.，持续8周）后1周开始。通过调节前列腺素E2的生物合成、EP 1和EP 2的表达和增殖，饮食中的匹伐他汀在晚上10点显著降低了舌头的发病率和多样性，但没有降低食管肿瘤的发病率和多样性。因此，我们的研究结果表明，rasH 2小鼠模型的4-NQO诱导的舌和食管癌的发生，可用于调查这些组织中的癌症发展的发病机制，并可能被证明是有用的，用于确定候选癌症化学预防剂的上消化器官。
We investigated the susceptibility of 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in male CB6F1-Tg-rasH2 @Jcl mice (Tg mice). The Tg mice were administered 4-NQO (20 p.p.m. in drinking water) for 2, 4, 6 or 8 weeks, and thereafter they were untreated up to week 24. At week 24, a higher incidence (80%) of tongue neoplasm with dysplasia was noted in the mice that received 4-NQO for 8 weeks in comparison with the other groups (20% incidence for each) treated with 4-NQO for 2, 4 and 6 weeks. Esophageal tumors also developed in the Tg mice were 4-NQO. Immunohistochemical observation revealed that the EP receptors, especially EP1 and EP2, expressed in the tongue and esophageal lesions induced by 4-NQO, thus suggesting the involvement of prostaglandin (PG) E-2 and EP1,2 receptors in the tongue and esophageal carcinogenesis. Using this animal model, we investigated the potential chemopreventive ability of pitavastatin (1, 5 and 10 p.p.m. in diet for 15 weeks), starting 1 week after the cessation of 4-NQO-exposure (20 p.p.m. in drinking water for 8 weeks). Dietary pitavastatin at 10 p.p.m. significantly reduced the incidence and multiplicity of the tongue, but not esophageal neoplasms by the modulation of prostaglandin E2 biosynthesis, EP1 and EP2 expression and proliferation. Our results thus suggest that a rasH2 mouse model of 4-NQO-induced tongue and esophageal carcinogenesis can be utilized for investigating the pathogenesis of cancer development in these tissues and may well prove to be useful for identifying candidate cancer chemopreventive agents for the upper digestive organs.