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Clin Cancer Res. 2010 Sep 15;16(18):4561-71. doi: 10.1158/1078-0432.CCR-10-0593. Epub 2010 Sep 7.

Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer.

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  • 1Institue of Biochemistry, National Chung-Hsing University, Taichung, Taiwan.

Abstract

PURPOSE:

We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).

EXPERIMENTAL DESIGN:

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.

©2010 AACR.

PMID:
20823140
[PubMed - indexed for MEDLINE]
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