title: Cell cycle association and hypoxia regulation of excision repair cross complementation group 1 protein (ERCC1) in tumor cells of head and neck cancer.
abstract: Excision repair cross complementation group 1 (ERCC1) is a key component of homologous recombination-based repair of interstrand DNA cross-links (ICLs). As a consequence, ERCC1 mediates resistance to mitomycin C (MMC) and platinum chemotherapeutic agents and may predict treatment failure. Clinical response to MMC or cisplatin (CDDP)-based radiochemotherapy (RCT) was assessed in 106 head and neck squamous cell carcinoma (HNSCC) patients and correlated with cell nuclear immunoreactivity of the mouse monoclonal (clone: 8 F1) ERCC1 antibody in tumor tissue samples. BEAS-2B epithelial and Detroit 562 pharyngeal squamous carcinoma cells were treated with CDDP, MMC, and 5-fluorouracil (5-FU) at 50 % growth inhibitory (IC-50) concentrations. ERCC1 protein synthesis was compared with cell cycle distribution using combined immunocytochemistry and flow cytometry. ERCC1 messenger RNA (mRNA) and protein expression was investigated in normoxic and hypoxic conditions in Detroit 562 cells. Clinically, the nonresponder revealed significantly lower HNSCC tissue ERCC1 immunoreactivity than the responder (p = 0.0064) or control normal mucosa, which led to further mechanistic investigations. In vitro, control cells and cells treated with cytotoxic agents showed increasing ERCC1 levels from the G1 through S and G2 phases of the cell cycle. In CDDP-treated cells, ERCC1 mRNA and protein expression increased. Under hypoxic conditions, ERCC1 gene expression significantly decreased. Although ERCC1(+) cells show increased chemoresistance, they might be particularly radiosensitive, representing G2 cell cycle phase and less hypoxic. ERCC1 expression might be indirectly related with some conditions important for RCT treatment, but it is not a clear predictor for its failure in HNSCC patients.
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria, jozsef.dudas@i-med.ac.at.
authors.forename: József
authors.initials: J
authors.lastname: Dudás
authors.forename: Volker H
authors.initials: VH
authors.lastname: Schartinger
authors.forename: Angela
authors.initials: A
authors.lastname: Romani
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schweigl
authors.forename: Kristian
authors.initials: K
authors.lastname: Kordsmeyer
authors.forename: Patricia Irina
authors.initials: PI
authors.lastname: Marta
authors.forename: Christoph
authors.initials: C
authors.lastname: Url
authors.forename: Florian
authors.initials: F
authors.lastname: Kral
authors.forename: Herbert
authors.initials: H
authors.lastname: Riechelmann
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000473:pathology* / Q000628:therapy; D002453:Cell Cycle; D015687:Cell Hypoxia; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004720:Endonucleases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D000077195:Squamous Cell Carcinoma of Head and Neck; D017211:Treatment Failure
chemical_list: D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin