Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development  

作　　者：Xiaoli Zhang Nonggao He Dongsheng Gu Jeff Wickliffe James Salazar Istavan Boldogh Jingwu Xie 

机构地区：[1]Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine [2]University of Texas Medical Branch, School of Medicine Cancer Center [3]Department of Global Environmental Health Sciences, Tulane University School of Public Health [4]Biology Department, Galveston College [5]Department of Microbiology and Immunology, University of Texas Medical Branch, School of Medicine

出　　处：《Journal of Genetics and Genomics》2015年第10期589-596,共8页遗传学报（英文版）

基　　金：supported by National Cancer Institute (Nos. R01CA155086 and R01CA94160) to J. Xie,;National Institute of Environmental Sciences (No. RO1 ES018948) to I. Boldorgh

摘　　要：Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C （XPC） are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog （Kras） or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, KrasTM, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasTM and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured ceils, we demonstrated that induced expression of oncogenic KR.ASG12v led to increased levels of reactive oxygen species （ROS） as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C （XPC） are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog （Kras） or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer with these mutations. Using activated Kras, KrasTM, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasTM and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured ceils, we demonstrated that induced expression of oncogenic KR.ASG12v led to increased levels of reactive oxygen species （ROS） as well as DNA damage, and both can be suppressed by anti-oxidants. Our results suggest that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.

关 键 词：Lung cancer XPC KRAS ROS 

分 类 号：R734.2[医药卫生—肿瘤]