Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

Xiaoli Zhang, Nonggao He, Dongsheng Gu, Jeff Wickliffe, James Salazar, Istvan Boldogh, Jingwu Xie

Research output: Contribution to journalArticle

3 Citations (Scopus)

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, KrasLA1, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasLA1 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 KRASG12V 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.

Original languageEnglish (US)
Pages (from-to)589-596
Number of pages8
JournalJournal of Genetics and Genomics
Volume42
Issue number10
DOIs
StatePublished - Oct 20 2015

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Xeroderma Pigmentosum
Lung Neoplasms
DNA Damage
Reactive Oxygen Species
DNA Repair-Deficiency Disorders
Mutation
Oncogenes
Oxidants
DNA Repair
Sarcoma
Genes
Cause of Death
Colorectal Neoplasms
Cultured Cells
Prostatic Neoplasms
Survival Rate
Cell Count
Breast Neoplasms
Phenotype

Keywords

  • Kras
  • Lung cancer
  • ROS
  • XPC

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology

Cite this

Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development. / Zhang, Xiaoli; He, Nonggao; Gu, Dongsheng; Wickliffe, Jeff; Salazar, James; Boldogh, Istvan; Xie, Jingwu.

In: Journal of Genetics and Genomics, Vol. 42, No. 10, 20.10.2015, p. 589-596.

Research output: Contribution to journalArticle

Zhang, Xiaoli ; He, Nonggao ; Gu, Dongsheng ; Wickliffe, Jeff ; Salazar, James ; Boldogh, Istvan ; Xie, Jingwu. / Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development. In: Journal of Genetics and Genomics. 2015 ; Vol. 42, No. 10. pp. 589-596.
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