4-硝基喹啉-1-氧化物诱发大鼠舌黏膜鳞癌模型和分子发病机制研究进展

The animal model with tongue squamous cell carcinoma induced by 4NQO and its mechanism of molecular carcinogenesis

发展一种新的方法用来提高口腔癌的诊断和治疗效果,建立能够模拟人类口腔鳞癌自然发生的动物模型是必需的,应用4-硝基喹啉-1-氧化物(4-nitroquinoline-1-oxide,4NQO)诱导SD大鼠舌黏膜鳞癌是一种可靠的方法。水溶性喹啉衍生物4NQO可以形成DNA加成物,引起碱基的改变(G→A)或丢失突变。但4NQO要发挥这种诱变剂作用,需要在4NQO还原酶作用下将4NQO转化成4-羟氨基喹啉-1-氧化物及4-乙酰基喹啉-1-氧化物(4-AAQO),4-AAQO能够以共价键的方式结合到核酸上并破坏染色体的结构,进一步影响抑癌基因和癌基因表达。动物舌根黏膜该酶含量较高,所以可以靶向性在舌根形成癌。饮水中很低剂量的4NQO便可特异性在舌根形成癌,其形成过程和形态学变化都和人的口腔鳞癌发生过程十分相似,该模型是研究口腔癌发生和癌变机制的理想模型。

To develop a novel method and to improve the existing protocols for diagnosis and treatment,an animal model that mimics the natural course of human oral squamous cell carcinoma（SCC）is mandatory.The previous study revealed that application of 4-nitroquinoline-1-oxide（4NQO）to SD rat tongues was a reliable procedure for inducing oral SCCs.4NQO,a water-soluble quinoline derivative,has been extensively investigated and is known to cause the formation of DNA adducts.It induces basepair changes（G→A） and deletion mutations,then changes the expression levels of some oncogenes and tumor suppression genes.But this mutagenic action requires the conversion of 4NQO to 4-hydroxyaminoquinoline-1-oxide by 4NQO reductase,which binds covalently to nucleic acids and damages chromosomes.4NQO reductase expresses highly in the mucosa of the tongue root.4NQO can specifically induce tongue SCC when applied in low concentrations via drinking water.The resulting sequential changes and morphological features resemble those seen during the progression of human tongue squamous cell malignancy.Therefore,4NQO-induced rat tongue SCC is an excellent model for studying early events and molecular mechanism in oral carcinogenesis.