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. 2018 May 1;13(5):e0196681.
doi: 10.1371/journal.pone.0196681. eCollection 2018.

Identification of cancer-related miRNA-lncRNA biomarkers using a basic miRNA-lncRNA network

Guangle Zhang  1 , Cong Pian  2 , Zhi Chen  1 , Jin Zhang  1 , Mingmin Xu  1 , Liangyun Zhang  1 , Yuanyuan Chen  1
Affiliations

Identification of cancer-related miRNA-lncRNA biomarkers using a basic miRNA-lncRNA network

Guangle Zhang et al. PLoS One. .

Abstract

LncRNAs are regulatory noncoding RNAs that play crucial roles in many biological processes. The dysregulation of lncRNA is thought to be involved in many complex diseases; lncRNAs are often the targets of miRNAs in the indirect regulation of gene expression. Numerous studies have indicated that miRNA-lncRNA interactions are closely related to the occurrence and development of cancers. Thus, it is important to develop an effective method for the identification of cancer-related miRNA-lncRNA interactions. In this study, we compiled 155653 experimentally validated and predicted miRNA-lncRNA associations, which we defined as basic interactions. We next constructed an individual-specific miRNA-lncRNA network (ISMLN) for each cancer sample and a basic miRNA-lncRNA network (BMLN) for each type of cancer by examining the expression profiles of miRNAs and lncRNAs in the TCGA (The Cancer Genome Atlas) database. We then selected potential miRNA-lncRNA biomarkers based on the BLMN. Using this method, we identified cancer-related miRNA-lncRNA biomarkers and modules specific to a certain cancer. This method of profiling will contribute to the diagnosis and treatment of cancers at the level of gene regulatory networks.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flowchart detailing the construction of an individual-specific miRNA-lncRNA network (ISMLN).
(A) Construction of the reference miRNA-lncRNA network. After selecting n non-tumor samples as the reference samples and 155653 miRNA-lncRNA associations as the basic edges, the reference network is constructed by computing the Pearson Correlation Coefficients (PCCs) based on miRNA and lncRNA expression data. (B) After the addition of the n+1th sample, which is a tumor sample, to the reference network, a perturbed miRNA-lncRNA network is built by calculating the PCCs. The difference between the above two miRNA-lncRNA networks is regarded as the individual-specific miRNA-lncRNA network (ISMLN).
Fig 2
Fig 2. The BMLN for each type of cancer.
Taking BRCA as an example, we obtained 508 ISMLNs. We then counted the number of samples with significant changes for each miRNA-lncRNA pair and calculated the significance score. For example, the miR-200a-XIST interaction was significantly altered in all 508 samples, so the corresponding significance score was 508/508 = 1. Similarly, the significance scores of all 155653 miRNA-lncRNA pairs were calculated. We then ranked the miRNA-lncRNA pairs in descending order based on their significance scores. Finally, we chose only the miRNA-lncRNA interactions with high scores for further analysis.
Fig 3
Fig 3. Entire flowchart.
Fig 4
Fig 4. The distribution of ΔPCC values.
The cutoff of significant ΔPCC are X = 0.332 and X = -0.332, respectively. The red curve is the normal distribution curve of ΔPCC.
Fig 5
Fig 5. ROC of distinct features.
A-F show the ROC curves of classification results that take the top 1, 2, 3, 4, or 5 and last 5 potential miRNA-lncRNA edge biomarkers and the differentially expressed RNAs as the features, respectively.
Fig 6
Fig 6. Volcano plots of potential miRNA and lncRNA edge biomarkers.
(A) Volcano plot of potential miRNA edge biomarkers. (B) Volcano plot of potential lncRNA edge biomarkers. Green nodes represent RNAs that are not differentially expressed, red nodes represent RNAs that are downregulated, and blue nodes represent RNAs that are upregulated.
Fig 7
Fig 7. Activity Scores of candidate edge biomarker miRNAs.
(A) The top 50 Activity Scores of miRNAs participating in potential miRNA-lncRNA biomarkers in BMLN of BRCA. (B) The categories of top 50 miRNAs based on the Activity Score in BMLN of BRCA.
Fig 8
Fig 8
(A) A heat map of the top 200 miRNA-lncRNA interactions in the six types of cancers. Each column represents a cancer, and each row represents the significance score of the corresponding miRNA-lncRNA pair. The redder the color, the greater the significance score of the corresponding pair. (B) The distribution of lncRNA biomarkers involved in the top 200 edge biomarkers in distinct cancers.
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