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Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer.

He DX, Gu F, Gao F, Hao JJ, Gong D, Gu XT, Mao AQ, Jin J, Fu L, Ma X - Sci Rep (2016)

Bottom Line: Cancer chemoresistance is regulated by complex genetic and epigenetic networks.In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX).In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.

View Article: PubMed Central - PubMed

Affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China.

ABSTRACT
Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.

No MeSH data available.


Related in: MedlinePlus

Integration of RRBS, mRNA-Seq, and sRNA-Seq.(a) Genes whose expression was negatively associated with promoter methylation were used in the integration. Left lanes of the heat map are gene-expression values in MCF-7/ADM (left panel) and /PTX (right panel) versus /WT cells; middle lanes are the DMR values for each gene; right lanes are the expression of predicted miRNAs targeting each gene. (b) Venn diagrams of genes both regulated by methylation and miRNA in resistant versus sensitive comparison groups.
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f3: Integration of RRBS, mRNA-Seq, and sRNA-Seq.(a) Genes whose expression was negatively associated with promoter methylation were used in the integration. Left lanes of the heat map are gene-expression values in MCF-7/ADM (left panel) and /PTX (right panel) versus /WT cells; middle lanes are the DMR values for each gene; right lanes are the expression of predicted miRNAs targeting each gene. (b) Venn diagrams of genes both regulated by methylation and miRNA in resistant versus sensitive comparison groups.

Mentions: In the final step of high-throughput data integration, we investigated both pre- and post-transcriptional control of single genes during the acquisition of chemoresistance by combining mRNA-Seq, RRBS, and sRNA-Seq data (Table S6). In the MCF-7/ADM versus WT and MCF-7/PTX versus WT comparison groups, 223 and 240 genes with considerable overlaps were generated, respectively (Fig. 3a,b). The expression of genes in these lists was negatively correlated with promoter methylation (gene-body methylation was excluded from this part of the analysis because its regulatory mechanism is more complicated than promoter methylation). Meanwhile, all of the miRNAs predicted to target certain genes were listed, and the expression of each gene was negatively regulated by at least one miRNA.


Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer.

He DX, Gu F, Gao F, Hao JJ, Gong D, Gu XT, Mao AQ, Jin J, Fu L, Ma X - Sci Rep (2016)

Integration of RRBS, mRNA-Seq, and sRNA-Seq.(a) Genes whose expression was negatively associated with promoter methylation were used in the integration. Left lanes of the heat map are gene-expression values in MCF-7/ADM (left panel) and /PTX (right panel) versus /WT cells; middle lanes are the DMR values for each gene; right lanes are the expression of predicted miRNAs targeting each gene. (b) Venn diagrams of genes both regulated by methylation and miRNA in resistant versus sensitive comparison groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837395&req=5

f3: Integration of RRBS, mRNA-Seq, and sRNA-Seq.(a) Genes whose expression was negatively associated with promoter methylation were used in the integration. Left lanes of the heat map are gene-expression values in MCF-7/ADM (left panel) and /PTX (right panel) versus /WT cells; middle lanes are the DMR values for each gene; right lanes are the expression of predicted miRNAs targeting each gene. (b) Venn diagrams of genes both regulated by methylation and miRNA in resistant versus sensitive comparison groups.
Mentions: In the final step of high-throughput data integration, we investigated both pre- and post-transcriptional control of single genes during the acquisition of chemoresistance by combining mRNA-Seq, RRBS, and sRNA-Seq data (Table S6). In the MCF-7/ADM versus WT and MCF-7/PTX versus WT comparison groups, 223 and 240 genes with considerable overlaps were generated, respectively (Fig. 3a,b). The expression of genes in these lists was negatively correlated with promoter methylation (gene-body methylation was excluded from this part of the analysis because its regulatory mechanism is more complicated than promoter methylation). Meanwhile, all of the miRNAs predicted to target certain genes were listed, and the expression of each gene was negatively regulated by at least one miRNA.

Bottom Line: Cancer chemoresistance is regulated by complex genetic and epigenetic networks.In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX).In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.

View Article: PubMed Central - PubMed

Affiliation: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China.

ABSTRACT
Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.

No MeSH data available.


Related in: MedlinePlus