Li Zhixin, Peng Zhiqiang, Gu Siyu, Zheng Junfang, Feng Duiping, Qin Qiong, He Junqi
Basic Medicine Sciences Class of 2014, Capital Medical University, Beijing, P.R. China.
Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, P.R. China.
Anticancer Res. 2017 Aug;37(8):4455-4468. doi: 10.21873/anticanres.11841.
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.
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.
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.
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.
微小RNA（miRNA）与包括乳腺癌在内的多种癌症类型相关。晚期乳腺癌患者脑转移发生率为10%-30%，且与预后不良相关。miRNA在乳腺癌脑转移诊断和治疗中的潜在应用是一个备受关注的领域。为了初步系统地研究原发性乳腺癌中miRNA和mRNA的差异表达，这可能为脑转移的早期检测提供线索，我们分析了通过微阵列从原位癌患者和脑转移患者获得的基因表达综合数据库（GEO）数据集中基因表达全局模式的相应变化。
在乳腺癌脑转移患者的标本中研究miRNA-通路调控网络和miRNA-mRNA调控网络，以筛选出显著失调的miRNA，随后通过基因本体论（GO）分析预测其靶基因和通路。
基因表达变化的功能协调性可由单个miRNA调节。已鉴定出两种miRNA，即hsa-miR-17-5p和hsa-miR-16-5p，它们与靶mRNA[如B细胞淋巴瘤2（BCL2）、小体型/抗五聚体蛋白3（SMAD3）和细胞因子信号传导抑制因子1（SOCS1）]以及与上皮-间质转化和其他与癌症转移相关过程（包括细胞周期、黏附连接和细胞外基质-受体相互作用）的通路关联度最高。发现两个基因[含HECT、UBA和WWE结构域1（HUWE1）和BCL2]的mRNA与miRNA关联度最高，它们在乳腺癌脑转移标本中表达下调。在癌症基因组图谱（TCGA）乳腺癌数据集中验证了11种选定miRNA的变化。在TCGA的三阴性乳腺癌组织中检测到hsa-miR-17-5p上调。此外，在TCGA乳腺癌标本中发现hsa-miR-17-5p与总生存期以及磷酸酶和张力蛋白同源物（PTEN）和BCL2靶基因呈负相关。
我们的研究结果提供了不同家族miRNA的功能协调表达模式，可能有潜力从系统而非单基因角度为临床医生提供治疗乳腺癌脑转移的策略。
