title: Impaired nucleotide excision repair pathway as a possible factor in pathogenesis of head and neck cancer.
abstract: Tobacco smoking is one of the major risk factors in pathogenesis of head and neck squamous cell carcinomas (HNSCC). Many of the chemical compounds present in tobacco are well-known carcinogens which form adducts with DNA. Cells remove these adducts mainly by the nucleotide excision repair pathway (NER). NER also eliminates a broad spectrum of pyrimidine dimers (CPD) and photo-products (6-4PP) induced by UV-radiation or DNA cross-links after cisplatin anti-cancer treatment. In this study DNA damage and repair was examined in peripheral blood lymphocytes obtained from 20 HNSCC patients and 20 healthy controls as well as HTB-43 larynx and SSC-25 tongue cancer cell lines. DNA repair kinetics in the examined cells after cisplatin or UV-radiation treatment were investigated using alkaline comet assay during 240min of post-treatment incubation. MTT assay was used to analyse cell viability and the Annexin V-FITC kit specific for kinase-3 was employed to determine apoptosis after treating the cells with UV-radiation at dose range from 0.5 to 60J/m(2). NER capability was assessed in vitro with cell extracts by the use of a bacterial plasmid irradiated with UV-light as a substrate for the repair. The results show that lymphocytes from HNSCC patients and HTB-43 or SSC-25 cancer cells were more sensitive to genotoxic treatment with UV-radiation and displayed impaired DNA repair. Also evidenced was a higher rate of apoptosis induction after UV-radiation treatment of lymphocytes from the HNSCC patients and the HTB-43 cancer cells than after treatment of those from healthy donors. Finally, our results showed that there was a significant decrease in NER capacity in HTB-43 or SSC-25 cancer cells as well as in peripheral blood lymphocytes of HNSCC patients compared to controls. In conclusion, we suggest that the impaired NER pathway might be a critical factor in pathogenesis of head and neck cancer.
authors.affiliation: Department of Molecular Genetics, University of Lodz, Lodz, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Sliwinski
authors.forename: L
authors.initials: L
authors.lastname: Markiewicz
authors.forename: P
authors.initials: P
authors.lastname: Rusin
authors.forename: J
authors.initials: J
authors.lastname: Kabzinski
authors.forename: L
authors.initials: L
authors.lastname: Dziki
authors.forename: J
authors.initials: J
authors.lastname: Milonski
authors.forename: J
authors.initials: J
authors.lastname: Olszewski
authors.forename: J
authors.initials: J
authors.lastname: Blaszczyk
authors.forename: J
authors.initials: J
authors.lastname: Szemraj
authors.forename: I
authors.initials: I
authors.lastname: Majsterek
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077195:Squamous Cell Carcinoma of Head and Neck; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D002945:Cisplatin