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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

Cross-matching of sequencing data.(a) Venn diagrams of the differentially-expressed genes cross-matched with the DMRs in their promoter and 5′UTR regions in the three comparison groups. Genes were chosen when their expression changes were negatively associated with changes in the DMRs in chemoresistant cells versus MCF-7/WT cells. (b) Venn diagrams of the differentially-expressed miRNAs cross-matched with DMRs around the miRNA coding sequence in the three comparison groups. (c) Up- or down-regulated miRNAs were integrated with the overall methylation level when comparing resistant with sensitive cells. Red bars, overall methylation levels (Y axis) of up-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells; green bars, overall methylation levels of down-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells. (d) Locations of the DMRs relative to the TSS of each miRNA. X axis, Log2 values of DMRs (resistant versus sensitive); Y axis, their locations relative to the TSS.
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f2: Cross-matching of sequencing data.(a) Venn diagrams of the differentially-expressed genes cross-matched with the DMRs in their promoter and 5′UTR regions in the three comparison groups. Genes were chosen when their expression changes were negatively associated with changes in the DMRs in chemoresistant cells versus MCF-7/WT cells. (b) Venn diagrams of the differentially-expressed miRNAs cross-matched with DMRs around the miRNA coding sequence in the three comparison groups. (c) Up- or down-regulated miRNAs were integrated with the overall methylation level when comparing resistant with sensitive cells. Red bars, overall methylation levels (Y axis) of up-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells; green bars, overall methylation levels of down-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells. (d) Locations of the DMRs relative to the TSS of each miRNA. X axis, Log2 values of DMRs (resistant versus sensitive); Y axis, their locations relative to the TSS.

Mentions: Consistent with the widely-accepted mechanism of methylation11, the expression of 1083 and 213 genes in both MCF-7/ADM and /PTX cells was negatively correlated with the levels of promoter and 5′UTR methylation, respectively, versus MCF-7/WT cells (Fig. 2a). This suggested that methylation plays a role in gene-silencing during the acquisition of chemoresistance. The mechanism by which methylation regulates expression in the gene-body is complicated, but more than half of these regions were positively correlated with gene expression as previously suggested (Table S2)12.


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)

Cross-matching of sequencing data.(a) Venn diagrams of the differentially-expressed genes cross-matched with the DMRs in their promoter and 5′UTR regions in the three comparison groups. Genes were chosen when their expression changes were negatively associated with changes in the DMRs in chemoresistant cells versus MCF-7/WT cells. (b) Venn diagrams of the differentially-expressed miRNAs cross-matched with DMRs around the miRNA coding sequence in the three comparison groups. (c) Up- or down-regulated miRNAs were integrated with the overall methylation level when comparing resistant with sensitive cells. Red bars, overall methylation levels (Y axis) of up-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells; green bars, overall methylation levels of down-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells. (d) Locations of the DMRs relative to the TSS of each miRNA. X axis, Log2 values of DMRs (resistant versus sensitive); Y axis, their locations relative to the TSS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Cross-matching of sequencing data.(a) Venn diagrams of the differentially-expressed genes cross-matched with the DMRs in their promoter and 5′UTR regions in the three comparison groups. Genes were chosen when their expression changes were negatively associated with changes in the DMRs in chemoresistant cells versus MCF-7/WT cells. (b) Venn diagrams of the differentially-expressed miRNAs cross-matched with DMRs around the miRNA coding sequence in the three comparison groups. (c) Up- or down-regulated miRNAs were integrated with the overall methylation level when comparing resistant with sensitive cells. Red bars, overall methylation levels (Y axis) of up-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells; green bars, overall methylation levels of down-regulated miRNAs in MCF-7/ADM or /PTX versus /WT cells. (d) Locations of the DMRs relative to the TSS of each miRNA. X axis, Log2 values of DMRs (resistant versus sensitive); Y axis, their locations relative to the TSS.
Mentions: Consistent with the widely-accepted mechanism of methylation11, the expression of 1083 and 213 genes in both MCF-7/ADM and /PTX cells was negatively correlated with the levels of promoter and 5′UTR methylation, respectively, versus MCF-7/WT cells (Fig. 2a). This suggested that methylation plays a role in gene-silencing during the acquisition of chemoresistance. The mechanism by which methylation regulates expression in the gene-body is complicated, but more than half of these regions were positively correlated with gene expression as previously suggested (Table S2)12.

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