{"doi":"10.18632/oncotarget.28724","title":"Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis","abstract":"// Nawar Al Nasrallah 1 , 4 , Bowa Lee 2 , Benjamin M. Wiese 1 , Marie N. Karam 2 , Elizabeth A. Mickler 1 , Huaxin Zhou 1 , Nicki Paolelli 1 , Robert S. Stearman 1 , Mark W. Geraci 3 and Catherine R. Sears 4 , 1 1 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis, IN 46202, USA 2 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 3 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA 4 Pulmonary Oncology, Pulmonary and Critical Care Section, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA Correspondence to: Catherine R. Sears, email: crufatto@iu.edu Keywords: DNA repair; DNA damage; lung adenocarcinoma; squamous cell carcinoma; Xeroderma Pigmentosum Group C (XPC) Received: January 13, 2025     Accepted: April 28, 2025     Published: May 20, 2025 Copyright: © 2025 Nasrallah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a “double hit“ mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response.","journal":"Oncotarget","year":2025,"id":541240,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1429986,"name":"Bowa Lee","orcid":null,"position":1,"is_corresponding":false},{"id":899280,"name":"Benjamin M. Wiese","orcid":null,"position":2,"is_corresponding":false},{"id":1429618,"name":"Marie Nour Karam","orcid":"0009-0005-4112-0513","position":3,"is_corresponding":false},{"id":436674,"name":"Elizabeth A. Mickler","orcid":null,"position":4,"is_corresponding":false},{"id":1429619,"name":"Huaxin Zhou","orcid":"0000-0002-2838-9199","position":5,"is_corresponding":false},{"id":1429987,"name":"Nicki Paolelli","orcid":null,"position":6,"is_corresponding":false},{"id":32242,"name":"Robert S. Stearman","orcid":"0000-0002-7628-7066","position":7,"is_corresponding":false},{"id":32255,"name":"Mark W. Geraci","orcid":"0000-0002-2280-3424","position":8,"is_corresponding":false},{"id":333353,"name":"Catherine R. Sears","orcid":"0000-0002-5797-3458","position":9,"is_corresponding":false},{"id":333354,"name":"Nawar Al Nasrallah","orcid":"0000-0002-6507-8859","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:52:47.161928Z","pmid":"40391767","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}