Department of Computer Engineering, Bilkent University, Ankara, 06800, Turkey.
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, 06800, Turkey.
BMC Genomics. 2018 Sep 4;19(1):650. doi: 10.1186/s12864-018-5006-1.
Long non-coding RNAs (lncRNAs) can indirectly regulate mRNAs expression levels by sequestering microRNAs (miRNAs), and act as competing endogenous RNAs (ceRNAs) or as sponges. Previous studies identified lncRNA-mediated sponge interactions in various cancers including the breast cancer. However, breast cancer subtypes are quite distinct in terms of their molecular profiles; therefore, ceRNAs are expected to be subtype-specific as well.
To find lncRNA-mediated ceRNA interactions in breast cancer subtypes, we develop an integrative approach. We conduct partial correlation analysis and kernel independence tests on patient gene expression profiles and further refine the candidate interactions with miRNA target information. We find that although there are sponges common to multiple subtypes, there are also distinct subtype-specific interactions. Functional enrichment of mRNAs that participate in these interactions highlights distinct biological processes for different subtypes. Interestingly, some of the ceRNAs also reside in close proximity in the genome; for example, those involving HOX genes, HOTAIR, miR-196a-1 and miR-196a-2. We also discover subtype-specific sponge interactions with high prognostic potential. We found that patients differ significantly in their survival distributions if they are group based on the expression patterns of specific ceRNA interactions. However, it is not the case if the expression of individual RNAs participating in ceRNA is used.
These results can help shed light on subtype-specific mechanisms of breast cancer, and the methodology developed herein can help uncover sponges in other diseases.
长非编码 RNA（lncRNA）可以通过结合 microRNA（miRNA）间接调节 mRNAs 的表达水平，充当竞争内源 RNA（ceRNA）或海绵。先前的研究已经确定了 lncRNA 在包括乳腺癌在内的各种癌症中介导的海绵相互作用。然而，乳腺癌亚型在分子特征方面有很大的不同；因此，ceRNA 预计也是亚型特异性的。
为了在乳腺癌亚型中找到 lncRNA 介导的 ceRNA 相互作用，我们开发了一种综合方法。我们对患者的基因表达谱进行偏相关分析和核独立性检验，并进一步利用 miRNA 靶标信息来细化候选相互作用。我们发现，虽然有多个亚型共有的海绵，但也有独特的亚型特异性相互作用。参与这些相互作用的 mRNAs 的功能富集突出了不同亚型的独特生物学过程。有趣的是，一些 ceRNA 也在基因组中紧密相邻；例如，涉及 HOX 基因、HOTAIR、miR-196a-1 和 miR-196a-2 的那些。我们还发现了具有高预后潜力的亚型特异性海绵相互作用。我们发现，如果根据特定 ceRNA 相互作用的表达模式对患者进行分组，他们在生存分布上存在显著差异。但是，如果使用参与 ceRNA 的单个 RNA 的表达，则不是这种情况。
这些结果可以帮助揭示乳腺癌亚型特异性的机制，并且本文开发的方法可以帮助揭示其他疾病中的海绵。
