Regulation of Excision Repair Cross-Complementation Group 1 by Snail Contributes to Cisplatin Resistance in Head and Neck Cancer

• Published in: Clinical cancer research Vol. 16; no. 18; pp. 4561 - 4571
• Main Authors: Hsu, Dennis Shin-Shian, Lan, Hsin-Yi, Huang, Chi-Hung, Tai, Shyh-Kuan, Chang, Shyue-Yih, Tsai, Tung-Lung, Chang, Cheng-Chi, Tzeng, Cheng-Hwai, Wu, Kou-Juey, Kao, Jung-Yie, Yang, Muh-Hwa
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2010
• Subjects: Antineoplastic agents; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - radiotherapy; Cell Line, Tumor; Cells, Cultured; Cisplatin - therapeutic use; DNA-Binding Proteins - genetics; Drug Resistance, Neoplasm - genetics; Endonucleases - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - radiotherapy; Humans; Medical sciences; Microarray Analysis; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Snail Family Transcription Factors; Survival Analysis; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Transfection; Tumors; Antineoplastic agent; Treatment resistance; Excision; Malignant tumor; In vitro; Cisplatin; Alkylating agent; Chemotherapy; Regulation(control); Treatment; Cell line; ENT disease; Head and neck cancer; Complementation; Repair; Tumor cell; Cancer; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-0593

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. Clin Cancer Res; 16(18); 4561–71. ©2010 AACR.