Li Kening, Liu Yongjing, Zhou Yuanshuai, Zhang Rui, Zhao Ning, Yan Zichuang, Zhang Qiang, Zhang Shujuan, Qiu Fujun, Xu Yan
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.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
Sci Rep. 2015 Jun 23;5:11567. doi: 10.1038/srep11567.
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.
已知拷贝数改变（CNA）主要通过剂量效应诱导基因表达变化，进而影响肿瘤的发生和发展。然而，由于转录调控机制复杂，肿瘤样本在基因剂量敏感性方面表现出异质性。目前，尚无高通量方法可用于鉴定影响CNA功能后果的调控因子，并确定它们对癌症的影响。鉴于miRNA的重要调控作用，我们研究了miRNA对CNA区域内基因剂量敏感性的影响。通过整合三种癌症的拷贝数、mRNA表达和miRNA表达谱，我们观察到高剂量敏感性基因在癌症中更易受到miRNA靶向的趋势，并鉴定出调控扩增/缺失靶基因剂量敏感性的miRNA。结果表明，miRNA可通过调控CNA区域内的基因来调节致癌生物学功能，从而在癌症中作为触发因素或平衡因素发挥作用，影响癌症进程甚至生存。这项工作提供了一个分析剂量效应调控的框架，将有助于理解CNA的致癌和抑癌机制。此外，还鉴定出了与癌症相关的新miRNA。
