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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

Comparison between the features of high sensitivity genes and low sensitivity genes.a: High sensitivity genes are regulated by more miRNAs.(single-tailed t test, results see Fig. 2c).b: High sensitivity genes have more miRNA binding sites. c: Details of the comparison results for the features of high sensitivity genes and low sensitivity genes. High-S and Low-S denotes for the set of high and low sensitivity genes, respectively. The P-value of Wilcoxon rank sum test was used to measure the differences between High-S and Low-S in the number of miRNAs and the degree in PPI network. The other P-values were calculated with the cumulative hypergeometric test.
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f2: Comparison between the features of high sensitivity genes and low sensitivity genes.a: High sensitivity genes are regulated by more miRNAs.(single-tailed t test, results see Fig. 2c).b: High sensitivity genes have more miRNA binding sites. c: Details of the comparison results for the features of high sensitivity genes and low sensitivity genes. High-S and Low-S denotes for the set of high and low sensitivity genes, respectively. The P-value of Wilcoxon rank sum test was used to measure the differences between High-S and Low-S in the number of miRNAs and the degree in PPI network. The other P-values were calculated with the cumulative hypergeometric test.

Mentions: We compared genes with high and low dosage sensitivity by the amount of miRNAs targeting them and the amount of miRNA binding sites in them based on the predicted miRNA-target in TargetScan and miRNA binding information in UCSC. As shown in Fig. 2, genes with high dosage sensitivity were targeted by more miRNAs (Fig. 2a), and had more miRNA binding sites (Fig. 2b). To deal with the high false positive rate of predicted miRNA targets and to ensure the correctness of our conclusions, we also investigated the dosage sensitivity of genes in the validated miRNA-gene pairs. The results showed that, in BRCA, GBM and OV, 58, 42 and 51 high dosage-sensitivity genes (high sensitivity genes for short) are confirmed to be regulated, but the numbers sharply reduced to 14, 2 and 7 when it comes to low dosage-sensitivity genes(low sensitivity genes for short). This indicated that high sensitivity genes (or driver genes) are under complicated and subtle post-transcriptional regulation. To determine whether the dosage sensitivity is correlated with gene length and 3’UTR length, we calculated the Pearson correlation coefficient (PCC) between them. The correlation between gene dosage sensitivity and gene length are similar in three types of cancers (BRCA: -0.052, GBM: -0.0056, OV: -0.022). And the correlation between gene dosage sensitivity and 3’UTR length were also very weak (BRCA: -0.013, GBM: -0.0079, OV: -0.0043). This indicates that the tendency of high sensitivity genes to be regulated by miRNAs is not due to their gene length or even 3’UTR length, but maybe more complicated functional and evolutionary reasons. Furthermore, we calculated the correlation between gene dosage sensitivity and mean of expression, the result showed that gene dosage sensitivity was not dependent on gene expression level. The correlations in three types of cancer were 0.045, -0.020 and 0.0021, respectively. In addition, we also found that the high dosage sensitivity genes in three types of cancer tend to have specific characteristics compared with low sensitivity genes (See Fig. 2c, Supplementary Fig. S3), suggesting their specific functional roles. In detail, high sensitivity genes (1) contained more cancer-related genes; (2) enriched to the geneset of genes encoding protein complexes; (3) exhibited higher connectivity in the PPI network; (4) enriched to essential genes; (5) depleted in drug target geneset, while low sensitivity genes were enriched to drug targets. That may be due to that many essential genes are in the high sensitivity group, the drugs targeting these genes can harm normal cells as well as cancer cells.


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)

Comparison between the features of high sensitivity genes and low sensitivity genes.a: High sensitivity genes are regulated by more miRNAs.(single-tailed t test, results see Fig. 2c).b: High sensitivity genes have more miRNA binding sites. c: Details of the comparison results for the features of high sensitivity genes and low sensitivity genes. High-S and Low-S denotes for the set of high and low sensitivity genes, respectively. The P-value of Wilcoxon rank sum test was used to measure the differences between High-S and Low-S in the number of miRNAs and the degree in PPI network. The other P-values were calculated with the cumulative hypergeometric test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Comparison between the features of high sensitivity genes and low sensitivity genes.a: High sensitivity genes are regulated by more miRNAs.(single-tailed t test, results see Fig. 2c).b: High sensitivity genes have more miRNA binding sites. c: Details of the comparison results for the features of high sensitivity genes and low sensitivity genes. High-S and Low-S denotes for the set of high and low sensitivity genes, respectively. The P-value of Wilcoxon rank sum test was used to measure the differences between High-S and Low-S in the number of miRNAs and the degree in PPI network. The other P-values were calculated with the cumulative hypergeometric test.
Mentions: We compared genes with high and low dosage sensitivity by the amount of miRNAs targeting them and the amount of miRNA binding sites in them based on the predicted miRNA-target in TargetScan and miRNA binding information in UCSC. As shown in Fig. 2, genes with high dosage sensitivity were targeted by more miRNAs (Fig. 2a), and had more miRNA binding sites (Fig. 2b). To deal with the high false positive rate of predicted miRNA targets and to ensure the correctness of our conclusions, we also investigated the dosage sensitivity of genes in the validated miRNA-gene pairs. The results showed that, in BRCA, GBM and OV, 58, 42 and 51 high dosage-sensitivity genes (high sensitivity genes for short) are confirmed to be regulated, but the numbers sharply reduced to 14, 2 and 7 when it comes to low dosage-sensitivity genes(low sensitivity genes for short). This indicated that high sensitivity genes (or driver genes) are under complicated and subtle post-transcriptional regulation. To determine whether the dosage sensitivity is correlated with gene length and 3’UTR length, we calculated the Pearson correlation coefficient (PCC) between them. The correlation between gene dosage sensitivity and gene length are similar in three types of cancers (BRCA: -0.052, GBM: -0.0056, OV: -0.022). And the correlation between gene dosage sensitivity and 3’UTR length were also very weak (BRCA: -0.013, GBM: -0.0079, OV: -0.0043). This indicates that the tendency of high sensitivity genes to be regulated by miRNAs is not due to their gene length or even 3’UTR length, but maybe more complicated functional and evolutionary reasons. Furthermore, we calculated the correlation between gene dosage sensitivity and mean of expression, the result showed that gene dosage sensitivity was not dependent on gene expression level. The correlations in three types of cancer were 0.045, -0.020 and 0.0021, respectively. In addition, we also found that the high dosage sensitivity genes in three types of cancer tend to have specific characteristics compared with low sensitivity genes (See Fig. 2c, Supplementary Fig. S3), suggesting their specific functional roles. In detail, high sensitivity genes (1) contained more cancer-related genes; (2) enriched to the geneset of genes encoding protein complexes; (3) exhibited higher connectivity in the PPI network; (4) enriched to essential genes; (5) depleted in drug target geneset, while low sensitivity genes were enriched to drug targets. That may be due to that many essential genes are in the high sensitivity group, the drugs targeting these genes can harm normal cells as well as cancer cells.

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