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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

miRNAs expressions relate to the dosage sensitivity of oncogenes/tumor suppressor genes in BRCA.a, b: The dosage sensitivity of amplified oncogene RAD51C in BRCA is related to the expression of hsa-miR-99a-5p and hsa-miR-100-5p. c: The dosage sensitivity of amplified oncogene AURKA in BRCA is related to the expression of let-7b-5p. d: The dosage sensitivity of deleted tumor suppressor gene YAP1 in BRCA is related to the expression of hsa-miR-375.
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f3: miRNAs expressions relate to the dosage sensitivity of oncogenes/tumor suppressor genes in BRCA.a, b: The dosage sensitivity of amplified oncogene RAD51C in BRCA is related to the expression of hsa-miR-99a-5p and hsa-miR-100-5p. c: The dosage sensitivity of amplified oncogene AURKA in BRCA is related to the expression of let-7b-5p. d: The dosage sensitivity of deleted tumor suppressor gene YAP1 in BRCA is related to the expression of hsa-miR-375.

Mentions: We found that, the dosage sensitivity of many amplified genes is significantly related to the expression of some of miRNAs targeting them. For example, RAD51C at 17q23 cooperate with BRCA1, BRCA2 in DNA damage response pathway3132, and is critical for G(2)/M checkpoint control32. RAD51C is repeatedly reported to be amplified in BRCA3334 and involved in the tumor process as a driver oncogene of BRCA3334. 117 in 310 samples (37.7%) showed RAD51C amplification, but only 39 amplified samples had increased expression. The expression of hsa-miR-100-5p and hsa-miR-99a-5p was significantly lower in dosage sensitive samples of RAD51C (single-tailed t-test p-value: 1.70E-5 and 4.10E-4, See Fig. 3a,b), leading to the decreased inhibition of oncogene RAD51C. In the dosage resistant samples of RAD51C, the expression of the two miRNAs were relatively higher, which counteracted the tendency of high expression of RAD51C. A poor survival was observed in samples with the low expression of hsa-miR-100-5p (Fig. 4a), may be due to the incomplete inhibition of the expression of RAD51C. The study of Gebeshuber et al. showed that hsa-miR-100-5p could inhibit breast tumorigenesis.48.7% samples (151/310) had shown AURKA amplification, in which 46 are dosage sensitive samples35. AURKA at 20q13 can encode aurora kinase A, which is an essential protein in microtubule formation and cell cycle. This gene was found to be associated with the subtyping and prognosis of breast cancer3637. We found that hsa-let-7b-5p may contribute to preventing the up-regulation of amplified AURKA (single-tailed t-test p value: 1.2E-3, See Fig. 3c), and help stabilize the expression of AURKA in the dosage resistant samples. Therefore, the high expression of hsa-let-7b-5p is speculated to have a role in suppressing tumorigenesis, as a balancer for cancer. We also found that samples with an overexpression of hsa-let-7b-5p had significant longer overall survival (Fig. 4b). Previous studies have proved its involvement in regulating on ER-alpha signaling in the ER-positive breast cancer38, regulating the self renewal and tumorigenicity of breast cancer cells39 and repressing cell proliferation pathways40, indicating its tumor suppressive role.


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)

miRNAs expressions relate to the dosage sensitivity of oncogenes/tumor suppressor genes in BRCA.a, b: The dosage sensitivity of amplified oncogene RAD51C in BRCA is related to the expression of hsa-miR-99a-5p and hsa-miR-100-5p. c: The dosage sensitivity of amplified oncogene AURKA in BRCA is related to the expression of let-7b-5p. d: The dosage sensitivity of deleted tumor suppressor gene YAP1 in BRCA is related to the expression of hsa-miR-375.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: miRNAs expressions relate to the dosage sensitivity of oncogenes/tumor suppressor genes in BRCA.a, b: The dosage sensitivity of amplified oncogene RAD51C in BRCA is related to the expression of hsa-miR-99a-5p and hsa-miR-100-5p. c: The dosage sensitivity of amplified oncogene AURKA in BRCA is related to the expression of let-7b-5p. d: The dosage sensitivity of deleted tumor suppressor gene YAP1 in BRCA is related to the expression of hsa-miR-375.
Mentions: We found that, the dosage sensitivity of many amplified genes is significantly related to the expression of some of miRNAs targeting them. For example, RAD51C at 17q23 cooperate with BRCA1, BRCA2 in DNA damage response pathway3132, and is critical for G(2)/M checkpoint control32. RAD51C is repeatedly reported to be amplified in BRCA3334 and involved in the tumor process as a driver oncogene of BRCA3334. 117 in 310 samples (37.7%) showed RAD51C amplification, but only 39 amplified samples had increased expression. The expression of hsa-miR-100-5p and hsa-miR-99a-5p was significantly lower in dosage sensitive samples of RAD51C (single-tailed t-test p-value: 1.70E-5 and 4.10E-4, See Fig. 3a,b), leading to the decreased inhibition of oncogene RAD51C. In the dosage resistant samples of RAD51C, the expression of the two miRNAs were relatively higher, which counteracted the tendency of high expression of RAD51C. A poor survival was observed in samples with the low expression of hsa-miR-100-5p (Fig. 4a), may be due to the incomplete inhibition of the expression of RAD51C. The study of Gebeshuber et al. showed that hsa-miR-100-5p could inhibit breast tumorigenesis.48.7% samples (151/310) had shown AURKA amplification, in which 46 are dosage sensitive samples35. AURKA at 20q13 can encode aurora kinase A, which is an essential protein in microtubule formation and cell cycle. This gene was found to be associated with the subtyping and prognosis of breast cancer3637. We found that hsa-let-7b-5p may contribute to preventing the up-regulation of amplified AURKA (single-tailed t-test p value: 1.2E-3, See Fig. 3c), and help stabilize the expression of AURKA in the dosage resistant samples. Therefore, the high expression of hsa-let-7b-5p is speculated to have a role in suppressing tumorigenesis, as a balancer for cancer. We also found that samples with an overexpression of hsa-let-7b-5p had significant longer overall survival (Fig. 4b). Previous studies have proved its involvement in regulating on ER-alpha signaling in the ER-positive breast cancer38, regulating the self renewal and tumorigenicity of breast cancer cells39 and repressing cell proliferation pathways40, indicating its tumor suppressive role.

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