title: Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development.
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(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.
authors.affiliation: Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: University of Texas Medical Branch, School of Medicine Cancer Center, Galveston, TX 77550, USA.
authors.forename: Nonggao
authors.initials: N
authors.lastname: He
authors.affiliation: Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Gu
authors.affiliation: Department of Global Environmental Health Sciences, Tulane University School of Public Health, New Orleans, LA 70112, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Wickliffe
authors.affiliation: Biology Department, Galveston College, Galveston, TX 77550, USA.
authors.forename: James
authors.initials: J
authors.lastname: Salazar
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, School of Medicine, Galveston, TX 77550, USA.
authors.forename: Istavan
authors.initials: I
authors.lastname: Boldogh
authors.affiliation: Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: jinxie@iu.edu.
authors.forename: Jingwu
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D014983:Xeroderma Pigmentosum / Q000378:metabolism*
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; Lung cancer; ROS; XPC