REV1 is implicated in the development of carcinogen-induced lung cancer.
REV1 is implicated in the development of carcinogen-induced lung cancer.
复制标题
Rev1与致癌物诱导的肺癌的发展有关。
DOI：
10.1158/1541-7786.mcr-08-0399
复制
发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
McGregor WG
中科院分区：
文献类型：
--
作者：
Dumstorf CA;Mukhopadhyay S;Krishnan E;Haribabu B;McGregor WG
癌症的体细胞突变假说预测，减少致癌物诱导的突变频率将降低癌症的发病率。为了检验这一点，我们开发了一种反突变策略，该策略基于对一种蛋白质水平的操纵，该蛋白质水平需要突变旁路由普遍存在的致癌物苯并[a]芘引起的DNA损伤。利用编码基因特异性靶向核酶的载体，这种蛋白Rev1在小鼠细胞中的表达减少。在后一种细胞中，苯并[a]芘的活化形式诱发的诱变作用降低了90%以上。为了检测Rev1转录本是否可以在体内降低，将该质粒与聚乙烯亚胺(一种非病毒阳离子聚合物)络合，并通过气雾剂传递到肺中。激光捕获显微切割细胞中实时定量聚合酶链式反应检测到的内源性Rev1转录本减少了60%。致癌物诱发小鼠肺肿瘤的多样性由6.4个/只明显降低到3.7个/只。此外，REV1抑制完全消除了27%暴露于致癌物的小鼠的肿瘤形成。这些数据支持跨病变合成途径在肺癌发生发展中的中心作用。此外，该通路成员的选择性调节为癌症预防提供了新的潜在靶点。
The somatic mutation hypothesis of cancer predicts that reducing the frequency of mutations induced by carcinogens will reduce the incidence of cancer. To examine this, we developed an antimutator strategy based on the manipulation of the level of a protein required for mutagenic bypass of DNA damage induced by the ubiquitous carcinogen benzo[a]pyrene. The expression of this protein, REV1, was reduced in mouse cells using a vector encoding a gene-specific targeting ribozyme. In the latter cells, mutagenesis induced by the activated form of benzo[a]pyrene was reduced over 90%. To examine if REV1 transcripts could be lowered in vivo, the plasmid was complexed with polyethyleneimine, a non-viral cationic polymer, and delivered to the lung via aerosol. The endogenous REV1 transcript in the bronchial epithelium as determined by quantitative real-time PCR in laser capture microdissected cells was reduced by 60%. There was a significant decrease in the multiplicity of carcinogen induced lung tumors from 6.4 tumors/ mouse to 3.7 tumors/ mouse. Additionally, REV1 inhibition completely abolished tumor formation in 27% of the carcinogen-exposed mice. These data support the central role of the translesion synthesis pathway in the development of lung cancer. Further, the selective modulation of members of this pathway presents novel potential targets for cancer prevention.