title: Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer.
abstract: OBJECTIVE
  We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy.
  
  
  RESULTS
  The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis.
  
  
  CONCLUSIONS
  Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells.
authors.affiliation: Institue of Biochemistry, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Dennis Shin-Shian
authors.initials: DS
authors.lastname: Hsu
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Shyue-Yih
authors.initials: SY
authors.lastname: Chang
authors.forename: Tung-Lung
authors.initials: TL
authors.lastname: Tsai
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
authors.forename: Jung-Yie
authors.initials: JY
authors.lastname: Kao
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D046228:Microarray Analysis; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin