Abstract
BackgroundRecent studies illuminated a novel role of microRNA (miRNA) in the competing endogenous RNA (ceRNA) interaction: two genes (ceRNAs) can achieve coexpression by competing for a pool of common targeting miRNAs. Individual biological investigations implied ceRNA interaction performs crucial oncogenic/tumor suppressive functions in glioblastoma multiforme (GBM). Yet, a systematic analysis has not been conducted to explore the functional landscape and prognostic significance of ceRNA interaction.ResultsIncorporating the knowledge that ceRNA interaction is highly condition-specific and modulated by the expressional abundance of miRNAs, we devised a ceRNA inference by differential correlation analysis to identify the miRNA-modulated ceRNA pairs. Analyzing sample-paired miRNA and gene expression profiles of GBM, our data showed that this alternative layer of gene interaction is essential in global information flow. Functional annotation analysis revealed its involvement in activated processes in brain, such as synaptic transmission, as well as critical tumor-associated functions. Notably, a systematic survival analysis suggested the strength of ceRNA-ceRNA interactions, rather than expressional abundance of individual ceRNAs, among three immune response genes (CCL22, IL2RB, and IRF4) is predictive of patient survival. The prognostic value was validated in two independent cohorts.ConclusionsThis work addresses the lack of a comprehensive exploration into the functional and prognostic relevance of ceRNA interaction in GBM. The proposed efficient and reliable method revealed its significance in GBM-related functions and prognosis. The highlighted roles of ceRNA interaction provide a basis for further biological and clinical investigations.
Highlights
Recent studies illuminated a novel role of microRNA in the competing endogenous RNA interaction: two genes can achieve coexpression by competing for a pool of common targeting miRNAs
Incorporating survival data, we discovered the prognostic significance of competing endogenous RNA (ceRNA) interactions among three immune response genes (CCL22, IL2RB, and IRF4), which was verified in two independent cohorts
Incorporating the findings from previous in vitro and in silico studies that ceRNA interaction is modulated by miRNA abundance, ceRNA inference by differential correlation analysis (CEIDCA) identifies a pair of ceRNAs that are significantly differentially correlated with each other with changes in miRNA expression levels (Fig. 1)
Summary
Incorporating the findings from previous in vitro and in silico studies that ceRNA interaction is modulated by miRNA abundance, CEIDCA identifies a pair of ceRNAs (ce-pair) that are significantly differentially correlated with each other with changes in miRNA expression levels (Fig. 1). Validation analysis of core ceRNA interactions We validated the core ce-triplets identified in TCGA (Fig. 2b) by an independent dataset of sample-matched miRNA and gene expression profiles (Chinese Glioma Genome Atlas (CGGA); n = 64) [38, 39]. Results of the three methods were highly comparable (Fig. 3a–b; Fisher’s exact test P-values ≤ 5.15×10-15 and ≤4.01×10-51 for identified ce-triplets and ceRNAs, respectively).
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