An integrative network-driven pipeline for systematic identification of lncRNA-associated regulatory network motifs in metastatic melanoma

Singh, Nivedita ; Eberhardt, Martin ; Wolkenhauer, Olaf ; Vera, Julio ; Gupta, Shailendra K. (2020-07-23)

CITATION: Singh, N., et al. 2020. An integrative network-driven pipeline for systematic identification of lncRNA-associated regulatory network motifs in metastatic melanoma. BMC Bioinformatics, 21:329, doi:10.1186/s12859-020-03656-6.

The original publication is available at https://bmcbioinformatics.biomedcentral.com

Article

Background: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal here is to study molecules associated with the cross-talk between various network layers, and their impact on tumor progression. Results: To elucidate their contribution to disease, we developed an integrative computational pipeline to construct and analyze a melanoma network focusing on lncRNAs, their miRNA and protein targets, miRNA target genes, and TFs regulating miRNAs. In the network, we identified three-node regulatory loops each composed of lncRNA, miRNA, and TF. To prioritize these motifs for their role in melanoma progression, we integrated patient-derived RNAseq dataset from TCGA (SKCM) melanoma cohort, using a weighted multi-objective function. We investigated the expression profile of the top-ranked motifs and used them to classify patients into metastatic and non-metastatic phenotypes. Conclusions: The results of this study showed that network motif UCA1/AKT1/hsamiR- 125b-1 has the highest prediction accuracy (ACC = 0.88) for discriminating metastatic and non-metastatic melanoma phenotypes. The observation is also confirmed by the progression-free survival analysis where the patient group characterized by the metastatic-type expression profile of the motif suffers a significant reduction in survival. The finding suggests a prognostic value of network motifs for the classification and treatment of melanoma.

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