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An integrated approach to reveal miRNAs' impacts on the functional consequence of copy number alterations in cancer.

Li K, Liu Y, Zhou Y, Zhang R, Zhao N, Yan Z, Zhang Q, Zhang S, Qiu F, Xu Y - Sci Rep (2015)

Bottom Line: Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer.The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival.Besides, new cancer-related miRNAs were identified.

View Article: PubMed Central - PubMed

Affiliation: 1] College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China [2] School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

ABSTRACT
Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified.

No MeSH data available.


Related in: MedlinePlus

Framework of the evaluation of dosage sensitivity and the identification of miRNAs that modulate dosage response.In the copy number matrix, yellow represents amplification, purple represents deletion. In the expression matrix of genes and miRNAs, red represents upregulation, blue represents downregulation. In the dosage sensitivity matrix, blue and red represents dosage sensitive samples with copy number deletion and amplification, respectively; and light blue and red represents dosage resistant samples with copy number deletion and amplification, respectively.
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f1: Framework of the evaluation of dosage sensitivity and the identification of miRNAs that modulate dosage response.In the copy number matrix, yellow represents amplification, purple represents deletion. In the expression matrix of genes and miRNAs, red represents upregulation, blue represents downregulation. In the dosage sensitivity matrix, blue and red represents dosage sensitive samples with copy number deletion and amplification, respectively; and light blue and red represents dosage resistant samples with copy number deletion and amplification, respectively.

Mentions: We acquired discrete copy number data from Ciriello et al.22 (Fig. 1). In the copy number profile, 1 represents an amplification of the gene, −1 represents a deletion, and 0 represents the normal diploid. We calculated the mean expression value and standard deviation (SD) of each gene across all samples. Gene expression values were divided into discrete levels, the values that are higher than mean + SD were set to 1, the values that are lower than mean-SD were set to −1, other values were set to 0. In this discrete expression matrix, 1 represents high expression, −1 represents low expression, and 0 is intermediate.


An integrated approach to reveal miRNAs' impacts on the functional consequence of copy number alterations in cancer.

Li K, Liu Y, Zhou Y, Zhang R, Zhao N, Yan Z, Zhang Q, Zhang S, Qiu F, Xu Y - Sci Rep (2015)

Framework of the evaluation of dosage sensitivity and the identification of miRNAs that modulate dosage response.In the copy number matrix, yellow represents amplification, purple represents deletion. In the expression matrix of genes and miRNAs, red represents upregulation, blue represents downregulation. In the dosage sensitivity matrix, blue and red represents dosage sensitive samples with copy number deletion and amplification, respectively; and light blue and red represents dosage resistant samples with copy number deletion and amplification, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477324&req=5

f1: Framework of the evaluation of dosage sensitivity and the identification of miRNAs that modulate dosage response.In the copy number matrix, yellow represents amplification, purple represents deletion. In the expression matrix of genes and miRNAs, red represents upregulation, blue represents downregulation. In the dosage sensitivity matrix, blue and red represents dosage sensitive samples with copy number deletion and amplification, respectively; and light blue and red represents dosage resistant samples with copy number deletion and amplification, respectively.
Mentions: We acquired discrete copy number data from Ciriello et al.22 (Fig. 1). In the copy number profile, 1 represents an amplification of the gene, −1 represents a deletion, and 0 represents the normal diploid. We calculated the mean expression value and standard deviation (SD) of each gene across all samples. Gene expression values were divided into discrete levels, the values that are higher than mean + SD were set to 1, the values that are lower than mean-SD were set to −1, other values were set to 0. In this discrete expression matrix, 1 represents high expression, −1 represents low expression, and 0 is intermediate.

Bottom Line: Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer.The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival.Besides, new cancer-related miRNAs were identified.

View Article: PubMed Central - PubMed

Affiliation: 1] College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China [2] School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

ABSTRACT
Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified.

No MeSH data available.


Related in: MedlinePlus