Cecilia Brown

DocwireNews

New research is “decoding the link” between the nucleotide excision repair protein XPC and lung cancer susceptibility in the setting of cigarette smoke exposure and may help illuminate the mechanisms of DNA damage, repair, and carcinogenesis in lung cancer.
A team from the Indiana University School of Medicine conducted the research and presented their findings during the American Thoracic Society 2024 International Conference. They explained the rationale behind the research, noting that “despite the known mutagenicity of cigarette smoke, only 10% to 15% of smokers will develop lung cancer in their lifetimes,” meaning “what determines a smoker’s susceptibility to lung cancer is poorly understood.”
The researchers identified the nucleotide excision repair protein XPC as a tumor suppressor “that may contribute to lung tumorigenesis when mutated and combined with cigarette smoke.” They hypothesized that cigarette smoke, combined with XPC knockdown, would cause genomic instability that activates the DNA damage response and increases the frequency of micronuclei and nuclear aberrancies.
The investigators used a human bronchial epithelial cell line (Beas-2B) and 2 lung adenocarcinoma cell lines (H1299 and A549) with stable XPC lentiviral knockdown (shXPC) or control shRNA (shCtrl). The cell lines were treated with cigarette smoke extract or air control. The researchers used a Western immunoblot to analyze DNA damage response proteins. They used a cytokinesis-block micronucleus assay with immunofluorescence microscopy to quantify micronuclei and nuclear aberrancies.
The study showed that cigarette smoke exposure and XPC knockdown independently amplified expression of DNA damage response proteins in all cell lines. In addition, nuclear aberrancies increased significantly (P&lt;.05) with cigarette smoke exposure in all 3 cell lines. The micronucleus frequency significantly increased with cigarette smoke exposure in the H1299 and Beas-2B cells (P&lt;.05) and with XPC knockdown in Beas-2B cells compared with shCtrl (P&lt;.001).
“We identified a previously uncharacterized role of XPC deficiency in augmenting [cigarette smoke]-induced chromosomal breaks manifesting as micronuclei,” the study authors explained. “XPC knockdown increased micronucleus frequency in noncancerous epithelial (Beas-2B), but not 2 lung adenocarcinoma cell lines, suggesting adenocarcinoma cells may depend on alternate DNA repair mechanisms to promote survival and avoid apoptosis.”
In addition, XPC deficiency was associated with “cell type-specific alterations in activation” of the DNA damage response.
The researchers explained that the study results suggest that XPC deficiency increases activation of the DNA damage response in both cancerous and noncancerous cell lines with cigarette smoke exposure.
“Overall, these findings offer insight into tumorigenesis in [cigarette smoke exposure conditions] and shed light on mechanisms of DNA damage, repair, and carcinogenesis. Accordingly, we propose a model whereby XPC mutations, compounded by [cigarette smoke], play an early role in lung tumor development,” the presenters concluded. “Future research should clarify the impact on genomic instability in human translational specimens and pinpoint additional functions of XPC beyond [nucleotide excision repair], including in base excision repair, replication repair, and the [DNA damage response].”
Reference
Karam M, Zhou H, Al Nasrallah N, Sears CR. Decoding the link between XPC and lung cancer susceptibility: a study of cigarette smoke-induced DNA damage in the setting of XPC deficiency. Presented at the American Thoracic Society 2024 International Conference; May 17-22, 2024; San Diego, California.

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Cigarette Smoke, DNA Damage, and XPC: Study Sheds Light on Lung Cancer Susceptibility

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New research is “decoding the link” between the nucleotide excision repair protein XPC and lung cancer susceptibility in the setting of cigarette smoke exposure.

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