Wu Qian, Guo Li, Jiang Fei, Li Lei, Li Zhong, Chen Feng
The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, Nanjing, China.
J Cell Mol Med. 2015 Dec;19(12):2874-87. doi: 10.1111/jcmm.12681. Epub 2015 Sep 28.
Recently, rapid advances in bioinformatics analysis have expanded our understanding of the transcriptome to a genome-wide level. miRNA-mRNA-lncRNA interactions have been shown to play critical regulatory role in cancer biology. In this study, we discussed the use of an integrated systematic approach to explore new facets of the oestrogen receptor (ER)-regulated transcriptome. The identification of RNAs that are related to the expression status of the ER may be useful in clinical therapy and prognosis. We used a network modelling strategy. First, microarray expression profiling of mRNA, lncRNA and miRNA was performed in MCF-7 (ER-positive) and MDA-MB-231 cells (ER- negative). A co-expression network was then built using co-expression relationships of the differentially expressed mRNAs and lncRNAs. Finally, the selected miRNA-mRNA network was added to the network. The key miRNA-mRNA-lncRNA interaction can be inferred from the network. The mRNA and non-coding RNA expression profiles of the cells with different ER phenotypes were distinct. Among the aberrantly expressed miRNAs, the expression levels of miR-19a-3p, miR-19b-3p and miR-130a-3p were much lower in the MCF-7 cells, whereas that of miR-148b-3p was much higher. In a cluster of miR-17-92, the expression levels of six of seven miRNAs were lower in the MCF-7 cells, in addition to miR-20b in the miR-106a-363 cluster. However, the levels of all the miRNAs in the miR-106a-25 cluster were higher in the MCF-7 cells. In the co-expression networking, CD74 and FMNL2 gene which is involved in the immune response and metastasis, respectively, had a stronger correlation with ER. Among the aberrantly expressed lncRNAs, lncRNA-DLEU1 was highly expressed in the MCF-7 cells. A statistical analysis revealed that there was a co-expression relationship between ESR1 and lncRNA-DLEU1. In addition, miR-19a and lncRNA-DLEU1 are both located on the human chromosome 13q. We speculate that miR-19a might be co-expressed with lncRNA-DLEU1 to co-regulate the expression of ESR1, which influences the occurrence and development of breast cancer cells with different levels of ER expression. Our findings reveal that the status of ER is mainly due to the differences in the mRNA and ncRNA profile between the breast cancer cell lines, and highlight the importance of studying the miRNA-mRNA-lncRNA interactions to completely illustrate the intricate transcriptome.
近年来，生物信息学分析的迅速发展将我们对转录组的理解扩展到了全基因组水平。已证明miRNA-mRNA-lncRNA相互作用在癌症生物学中发挥关键的调节作用。在本研究中，我们讨论了使用一种综合系统方法来探索雌激素受体（ER）调控转录组的新方面。鉴定与ER表达状态相关的RNA可能对临床治疗和预后有用。我们使用了一种网络建模策略。首先，在MCF-7（ER阳性）和MDA-MB-231细胞（ER阴性）中进行了mRNA、lncRNA和miRNA的微阵列表达谱分析。然后利用差异表达的mRNA和lncRNA的共表达关系构建了一个共表达网络。最后，将选定的miRNA-mRNA网络添加到该网络中。关键的miRNA-mRNA-lncRNA相互作用可从该网络中推断出来。具有不同ER表型的细胞的mRNA和非编码RNA表达谱是不同的。在异常表达的miRNA中，miR-19a-3p、miR-19b-3p和miR-130a-3p在MCF-7细胞中的表达水平要低得多，而miR-148b-3p的表达水平要高得多。在miR-17-92簇中，除了miR-106a-363簇中的miR-20b外，七个miRNA中有六个在MCF-7细胞中的表达水平较低。然而，miR-106a-25簇中所有miRNA的水平在MCF-7细胞中更高。在共表达网络中，分别参与免疫反应和转移的CD74和FMNL2基因与ER的相关性更强。在异常表达的lncRNA中，lncRNA-DLEU1在MCF-7细胞中高表达。统计分析表明ESR1和lncRNA-DLEU1之间存在共表达关系。此外，miR-19a和lncRNA-DLEU1都位于人类染色体13q上。我们推测miR-19a可能与lncRNA-DLEU1共表达以共同调节ESR1的表达，这影响了不同ER表达水平的乳腺癌细胞的发生和发展。我们的研究结果表明，ER的状态主要归因于乳腺癌细胞系之间mRNA和ncRNA谱的差异，并突出了研究miRNA-mRNA-lncRNA相互作用以全面阐明复杂转录组的重要性。
