Global Analysis of miRNA-mRNA Interaction Network in Breast Cancer with Brain Metastasis
Global Analysis of miRNA-mRNA Interaction Network in Breast Cancer with Brain Metastasis
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乳腺癌脑转移中 miRNA-mRNA 相互作用网络的整体分析
DOI：
10.21873/anticanres.11841
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发表时间：
2017-08-01
影响因子：
2
通讯作者：
He, Junqi
中科院分区：
文献类型：
--
作者：
Li, Zhixin;Peng, Zhiqiang;He, Junqi
背景：MicroRNAs（miRNAs）与包括乳腺癌在内的多种癌症类型有关。晚期乳腺癌患者脑转移率为10-30%，预后不良。miRNA在乳腺癌脑转移诊断和治疗中的潜在应用是一个非常感兴趣的领域。在最初的努力，以系统地解决的差异表达的miRNAs和mRNA在原发性乳腺癌，这可能会提供线索，早期发现脑转移，我们分析了随之而来的变化，在全球模式的基因表达基因表达的基因表达的Omnibus（GEO）数据集获得的微阵列从原位癌患者和脑转移患者。材料与方法：在脑转移患者的乳腺癌标本中研究miRNA通路调控网络和miRNA-mRNA调控网络，以筛选显著失调的miRNA，然后通过基因本体论（GO）分析预测其靶基因和通路。结果：单个miRNAs可以调控基因表达变化的功能协调。两种miRNAs，hsa-miR-17- 5 p和hsa-miR-16- 5 p，被鉴定为与靶向mRNA [如B细胞淋巴瘤2（BCL 2）、小体型/母亲抗十肢瘫痪3（SMAD 3）和细胞因子信号转导抑制因子1（SOCS 1）]以及与上皮-间充质转化相关的途径和与癌症转移相关的其他过程具有最高的关联性。（包括细胞周期、粘附连接和细胞外基质-受体相互作用）。发现两个基因[HECT、乌巴和WWE domain containing 1（HUWE 1）和BCL 2]的mRNA与miRNA的相关性最高，这两个基因在乳腺癌脑转移标本中下调。在癌症基因组图谱（TCGA）乳腺癌数据集中验证了11种选定的miRNA的变化。TCGA中三阴性乳腺癌组织中检测到hsa-miR-17- 5 p的上调。此外，在TCGA乳腺癌标本中发现hsa-miR-17- 5 p与总生存率以及磷酸酶和张力蛋白同源物（PTEN）和BCL 2靶基因呈负相关。结论：我们的研究结果提供了一个功能协调的表达模式的不同家族的miRNA，可能有潜力为临床医生提供一个策略，从系统，而不是一个单一的基因的角度来治疗乳腺癌脑转移。
Background: MicroRNAs (miRNAs) have been linked to a number of cancer types including breast cancer. The rate of brain metastases is 10-30% in patients with advanced breast cancer which is associated with poor prognosis. The potential application of miRNAs in the diagnostics and therapeutics of breast cancer with brain metastasis is an area of intense interest. In an initial effort to systematically address the differential expression of miRNAs and mRNAs in primary breast cancer which may provide clues for early detection of brain metastasis, we analyzed the consequent changes in global patterns of gene expression in Gene Expression Omnibus (GEO) data set obtained by microarray from patients with in situ carcinoma and patients with brain metastasis. Materials and Methods: The miRNA-pathway regulatory network and miRNA-mRNA regulatory network were investigated in breast cancer specimens from patients with brain metastasis to screen for significantly dysregulated miRNAs followed by prediction of their target genes and pathways by Gene Ontology (GO) analysis. Results: Functional coordination of the changes of gene expression can be modulated by individual miRNAs. Two miRNAs, hsa-miR-17-5p and hsa-miR-16-5p, were identified as having the highest associations with targeted mRNAs [such as B-cell lymphoma 2 (BCL2), small body size/mothers against decapentaplegic 3 (SMAD3) and suppressor of cytokine signaling 1 (SOCS1)] and pathways associated with epithelial-mesenchymal transitions and other processes linked with cancer metastasis (including cell cycle, adherence junctions and extracellular matrix-receptor interaction). mRNAs for two genes [HECT, UBA and WWE domain containing 1 (HUWE1) and BCL2] were found to have the highest associations with miRNAs, which were down-regulated in brain metastasis specimens of breast cancer. The change of 11 selected miRNAs was verified in The Cancer Genome Atlas (TCGA) breast cancer dataset. Up-regulation of hsa-miR-17-5p was detected in triple-negative breast cancer tissues in TCGA. Furthermore, a negative correlation of hsa-miR-17-5p with overall survival and phosphatase and tensin homolog (PTEN) and BCL2 target genes was found in TCGA breast cancer specimens. Conclusion: Our findings provide a functionally coordinated expression pattern of different families of miRNAs that may have potential to provide clinicians with a strategy to treat breast cancer with brain metastasis from a systems-rather than a single-gene perspective.