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

Kening Li,Fujun Qiu,Qiang Zhang,Yan Xu,Ning Zhao,Zichuang Yan,Rui Zhang,Yongjing Liu,Shujuan Zhang,Yuanshuai Zhou

doi:10.1038/srep11567

Kening Li, Fujun Qiu + Show 8 more

Open Access

https://doi.org/10.1038/srep11567

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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.

Highlights

Activation of oncogenes and inactivation of tumor suppressor genes are key mechanisms for tumor development
For the samples with Copy number alteration (CNA) of the same gene, the corresponding expression changes were observed only in some samples, indicating the heterogeneity of gene dosage sensitivity in different tumor samples
Ciriello et al discussed that GBM is developing mostly based on mutations, while ovarian cancer (OV) is based on CNAs22

Summary

Introduction

Activation of oncogenes and inactivation of tumor suppressor genes are key mechanisms for tumor development. We built a framework integrating mRNA expression, miRNA expression, copy number profiles and transcriptional regulatory relationships, to reveal the potential contributions of miRNAs to gene dosage sensitivity, and the consequence of these phenomena on oncogenesis and tumor suppression activities. We implement this framework on breast cancer, glioblastoma and ovarian cancer, and three main results are notable from this study: (1) The dosage sensitivity of genes in the three tumors are relatively weak. Genes with the highest dosage sensitivity conformed to the expectations for dosage effect in only about half of the CNA samples. (2) Genes with high dosage sensitivity have more miRNA binding sites and are targeted by more miRNAs. (3) We scored miRNAs based on their impact on amplified/deleted genes. miRNAs like hsa-let-7b-5p and hsa-miR-92a-3p were found to have significant influence on gene dosage sensitivity, the results of functional analysis and survival analysis indicated that they may be potential prognosis or therapy targets

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