Gene expression profiles of parental and chemotherapy-resistant colon cancer cell lines.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42387 | GEO | 2015/03/15
SECONDARY ACCESSION(S): PRJNA181264
REPOSITORIES: GEO
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Project description:Irinotecan, an analogue of camptothecin, is frequently used in combination with various anticancer drugs or as a single agent in treatment of colorectal cancer. But drug resistance of tumor is still a major obstacle to overcome for the success of cancer treatment. In this study, We established chronic irinotecan resistant cell line for new marker to increase the sensitivity to irinotecan and investigated gene expression profiles of the irinotecan-resistant colorectal cancer cell line.
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Project description:Purpose: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. Methods: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38- or oxaliplatin-resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of DNA methylation entropy to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. Results: We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences -- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.
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