Cyclin D1 in non-small cell lung cancer: A key driver of malignant transformation

被引:204
作者
Gautschi, Oliver
Ratschiller, Daniel
Gugger, Mathias
Betticher, Daniel C.
Heighway, Jim
机构
[1] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA
[2] Univ Hosp Bern, Clin Med Oncol, CH-3010 Bern, Switzerland
[3] Univ Hosp Bern, Dept Pathol, CH-3010 Bern, Switzerland
[4] Hosp Fribourg, Clin Med Oncol, Fribourg, Switzerland
[5] Canc Commun & Consultancy Ltd, Northwich, Cheshire, England
关键词
lung cancer; carcinogenesis; malignant transformation; oncogene; cyclin D1; cyclin dependent kinase; splicing; gene polymorphism; nuclear export; cancer risk;
D O I
10.1016/j.lungcan.2006.09.024
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention. Methods: Data published until June 2006 are summarized, and previously unpublished results from our own research are included. Results: In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A Low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cycolin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorytation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological rote for cyclin D1 deregulation in bronchial neoplasia. Conclusion: Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
引用
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页码:1 / 14
页数:14
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