Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

a.
Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
b.
University of Texas Medical Branch, School of Medicine Cancer Center, Galveston, TX 77550, USA
c.
Department of Global Environmental Health Sciences, Tulane University School of Public Health, New Orleans, LA 70112, USA
d.
Biology Department, Galveston College, Galveston, TX 77550, USA
e.
Department of Microbiology and Immunology, University of Texas Medical Branch, School of Medicine, Galveston, TX 77550, USA

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Corresponding author: E-mail address: jinxie@iu.edu (Jingwu Xie)

The first two authors contributed equally to this work.

摘要

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Abstract: 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, as a driver for lung cancer development in mice, we showed for the first time that mice with Kras 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.
- Lung cancer /
- XPC /
- ROS
The first two authors contributed equally to this work.
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