大鼠肺鳞癌中p16^(INK4a)和p19^(ARF)基因的缺失研究

Study of p16^(INK4a) and p19^(ARF) Gene Deletion in Rat Lung Squamous Cell Cancinoma

目的 :研究p16 INK4a和p19ARF基因的缺失与大鼠肺鳞癌发生发展的关系。方法 :利用显微切割和聚合酶链反应 (PCR)技术 ,在 10例正常大鼠支气管黏膜上皮细胞、16例癌前病变细胞和 34例肺鳞癌组织分别检测p16 INK4aE1α和p19ARFE1β的缺失。结果 :10例大鼠正常支气管黏膜上皮细胞均未发现有p16 INK4aE1α和p19ARFE1β的缺失。在 16例癌前病变中发现p16 INK4aE1α和p19ARFE1β缺失的检出率分别为 12 5 0 % (2 16 )和 6 2 5 % (1 16 ) ;p16 INK4aE1α或 (和 )p19ARFE1β总缺失率为 18 75 % (3 16 )。 34例大鼠肺鳞癌中p16 INK4aE1α和p19ARFE1β缺失的检出率分别为 32 35 % (11 34)和 4 1 18% (14 34) ,其中有 9例两者同时缺失 ,p16 INK4aE1α或 (和 )p19ARFE1β总缺失率为 4 7 0 6 % (16 34)。肺鳞癌的p19ARFE1β的缺失率显著高于癌前病变 ,P =0 0 12。结论 :在诱发性大鼠肺鳞癌的发生发展中 ,p16 INK4a基因的缺失可能在早期已起作用 ,p19ARF的生物学活性可能强于p16 INK4a。p16 INK4a和p19ARF基因的同时缺失损伤了Rb和p5 32条肿瘤抑制途径 。

Objective To investigate the relationship between p16 INK4a and p19 ARF gene deletions and induced rat lung squamous cell carcinogenesis.Methods Deletions of p16 INK4a and p19 ARF gene were detected by an optimized microdissection and a polymerase chain reaction in tissue samples from 10 normal bronchial epithelium,16 premalignant lesions and 34 lung squamous cell carcinomas.Results In 10 normal bronchial epithelium,deletions of p16 INK4a and p19 ARF gene were not observed.p16 INK4a E1α and p19 ARF E1β deletion rates were 12 50%(2/16) and 6 25%(1/16) respectively,with total rate of exon 1α and exon 1β deletion 18 75%(3/16) in 16 premalignant lesions.Exon 1α and exon 1β deletions were detected respectively in 32 35%(11/34) and 41 18%(14/34) lung cancers,simutaneous deletions of them were found in 9 lung cancers,total deletion rate of them was 47 06%(16/34) in lung cancers.Premalignant lesions versus lung cancers,there was significant difference in p19 ARF E1β deletion.Conclusions During the induced rat lung squamous cell carcinogenesis,deletion of the p16 INK4a gene plays an important role in early stage,the biology activity of p19 ARF is stronger than that of p16 INK4a .Simultaneous deletions of p16 INK4a and p19 ARF gene impair both the INK4a cyclinD/CDK4 Rb and ARF MDM2 p53 tumor suppressor pathways,and may contribute to malignant progression in rat lung squamous cell carcinoma.