Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

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• 作者：Xiaoli Zhang^a ; ¹ ; Nonggao He^b ; ¹ ; Dongsheng Gu^a ; Jeff Wickliffe^c ; James Salazar^d ; Istavan Boldogh^e ; Jingwu Xie^a ; ^{jinxie@iu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Lung cancer ; XPC ; Kras ; ROS
• 刊名：Journal of Genetics and Genomics
• 出版年：2015
• 出版时间：20 October 2015
• 年：2015
• 卷：42
• 期：10
• 页码：589-596
• 全文大小：1308 K

文摘

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, Kras^LA1, as a driver for lung cancer development in mice, we showed for the first time that mice with Kras^LA1 and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured cells, we demonstrated that induced expression of oncogenic KRAS^G12V 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.