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Gene expression profiling in A2780, CP70 and CP70 following Decitabine and/or PXD101 treatment

ABSTRACT: Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using gene expression profiling method on HGU133plus2 array, we identified a total of 1370 genes showing significant gene expression changes with 687 genes going up and 683 genes going down in the resistant (cp70) versus sensitive cell lines (A2780) by Rank Product (FDR<5%). Combining expression profiling with methylation profiling data we found out of 245 hypermethylated and down-regulated genes in the resistant cell line, 41 genes were up-regulated following Decitabine treatment alone, 45 genes up-regulated following combined treatment of Decitabine and PXD101, and only 10 genes up-regulated following PXD101 treatment alone. Altogether we found a small set of genes as being potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28646 | GEO | 2011/12/20

SECONDARY ACCESSION(S): PRJNA143075

REPOSITORIES: GEO

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Project description:Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using genome-wide DNA methylation profiling across 27,578 CpG sites on Illumina HumanMethylation27 bead array we identified loci at 4092 genes becoming hypermethylated in the chemoresistant A2780/cp70 ovarian tumour cell line compared to the parental sensitive A2780 line. Hypermethylation at CpG islands (CGI) is often associated with transcriptional silencing, however only 245 of these hypermethylated genes become down-regulated in A2780/cp70 as measured by microarray expression profiling. Treatment with the demethylating agent Decitabine induces re-sensitisation to cisplatin and resulted in re-expression of 41 of the down-regulated genes in cisplatin-resistant cells at the time point when re-sensitisation occurs. 13 of the 41 genes were consistently hypermethylated in two further independent cisplatin-resistant A2780 cell derivatives. Nine out of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS, PSMB9) acquired methylation at CpG sites in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 candidate genes acquired methylation in drug-resistant in vivo-derived ovarian cancer sustaining (side population) cells. Therefore, this small set of genes are potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in two cisplatin sensitive cell lines and three cisplatin resistant cell lines derived in vitro, four pairs of cisplatin sensitive and resistant cell lines derived in vivo, 7 pairs of tumour tissues obtained from patients before chemotherapy and at disease relapse, 2 pairs of IGROV1 SP and NSP cells. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using biological and technical replicates of matched chemosensitive/chemoresistant ovarian cancer cell lines PEO1/PEO4. Differential methylation cutoff was estimated from two biological replicates by bootstrap resampling.

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Gene expression profiling in A2780, CP70 and CP70 following Decitabine and/or PXD101 treatment

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