Oncogene, 2010-03, Vol.29 (11), p.1681-1690
2010
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- Autor(en) / Beteiligte
- Titel
- IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer
- Ist Teil von
- Oncogene, 2010-03, Vol.29 (11), p.1681-1690
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/onc.2009.454Titel-ID: cdi_proquest_miscellaneous_744616867
- Format
- –
- Schlagworte
- Antineoplastic Agents - pharmacology, Apoptosis, Azacitidine - pharmacology, Base Sequence, Binding proteins, Biological and medical sciences, Cancer therapies, Carcinoma, Non-Small-Cell Lung - genetics, Carcinoma, Non-Small-Cell Lung - metabolism, Carcinoma, Non-Small-Cell Lung - pathology, Cell Biology, Cell Line, Tumor, Cell physiology, Cell Survival - drug effects, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, Chemotherapy, Cisplatin, Cisplatin - pharmacology, Complications and side effects, Cytotoxicity, Deoxyribonucleic acid, DNA, DNA damage, DNA methylation, DNA Methylation - drug effects, DNA microarrays, Dosage and administration, Drug resistance, Drug Resistance, Neoplasm - genetics, Drug therapy, Epigenetics, Fundamental and applied biological sciences. Psychology, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Genetic aspects, Genetics, HeLa Cells, HT29 Cells, Human Genetics, Humans, Hydroxamic Acids - pharmacology, Insulin-Like Growth Factor Binding Protein 3 - deficiency, Insulin-Like Growth Factor Binding Protein 3 - genetics, Insulin-like growth factor-binding protein 3, Internal Medicine, Kaplan-Meier Estimate, Lung cancer, Lung cancer, Non-small cell, Lung Neoplasms - genetics, Lung Neoplasms - metabolism, Lung Neoplasms - pathology, Medical sciences, Medicine, Medicine & Public Health, Molecular and cellular biology, Non-small cell lung carcinoma, Oligonucleotide Array Sequence Analysis, Oncology, original-article, Patients, Phenotypes, Physiological aspects, Pneumology, Promoter Regions, Genetic - genetics, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, siRNA, Small cell lung carcinoma, Tumor cell lines, Tumor Cells, Cultured, Tumors, Tumors of the respiratory system and mediastinum