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Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development
Xiaoli Zhang1, Nonggao He2, Dongsheng Gu1
1Department of Pediatrics, Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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.
Insights
Xeroderma pigmentosum group C (XPC) deficiency worsens lung cancer outcomes by increasing DNA damage, particularly when oncogenic KRAS is present. Antioxidants may mitigate this damage, suggesting XPC plays a role in repairing KRAS-induced DNA lesions.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung cancer remains a leading cause of cancer-related mortality globally.
- While targeted therapies have improved outcomes for some lung adenocarcinomas, overall survival rates have stagnated.
- DNA repair gene polymorphisms, like those in xeroderma pigmentosum group C (XPC), are linked to lung cancer risk, but direct genetic evidence is limited.
Purpose of the Study:
- To investigate the direct genetic role of XPC in lung cancer development.
- To explore the relationship between XPC, Kirsten rat sarcoma viral oncogene homolog (Kras) mutations, and DNA damage in lung cancer.
- To determine if XPC deficiency exacerbates lung cancer progression driven by oncogenic Kras.
Main Methods:
- Utilized a mouse model with activated Kras (Kras(LA1)) to drive lung cancer development.
- Generated and analyzed Xpc knockout mice in conjunction with Kras(LA1).
- Employed cultured cells to study the effects of oncogenic KRAS(G12V) expression on reactive oxygen species (ROS) and DNA damage, assessing the impact of antioxidants.
Main Results:
- Mice with both Kras(LA1) and Xpc knockout exhibited significantly worse lung cancer outcomes.
- This exacerbated phenotype in Kras(LA1) and Xpc knockout mice was correlated with accumulated DNA damage.
- Induced expression of oncogenic KRAS(G12V) in cultured cells increased ROS and DNA damage, which were reduced by antioxidant treatment.
Conclusions:
- XPC deficiency worsens lung cancer progression, particularly in the context of Kras activation.
- Accumulated DNA damage, potentially mediated by KRAS-induced ROS, is a key factor in the observed phenotype.
- XPC may function to repair DNA damage resulting from ROS produced during KRAS-driven oncogenesis, highlighting a potential therapeutic target.
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