Abstract
Cisplatin-based chemotherapy is the paradigm of non-small-cell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (P<0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (P<0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment.
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Abbreviations
- ATCC:
-
American Type Culture Collection
- BS:
-
bisulfite sequencing
- CDDP:
-
cisplatin
- DFS:
-
disease-free survival
- ECACC:
-
European Collection of Cell Cultures
- IGFBP-3:
-
insulin-like growth factor binding protein-3
- MSP:
-
methylation-specific PCR
- NSCLC:
-
non-small-cell lung cancer
- TSG:
-
tumor suppressor gene
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Acknowledgements
We gratefully acknowledge Javier Perez for the artwork and to J Siegfried, for the English correction of the manuscript. Ibanez de Caceres was partially supported by the Fondo de Investigacion Sanitaria (ISCIII) through the ‘Miguel Servet’ program (CP 08/000689; PI-717). Note: Supported by FIS PI06-1234, PI08-1485, PS09/00472 and Fundación Médica Mutua Madrileña.
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Ibanez de Caceres, I., Cortes-Sempere, M., Moratilla, C. et al. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer. Oncogene 29, 1681–1690 (2010). https://doi.org/10.1038/onc.2009.454
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DOI: https://doi.org/10.1038/onc.2009.454
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