Pan-cancer analysis on microRNA-associated gene activation

BACKGROUND: While microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. METHODS: We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). FINDINGS: We found that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene plausibly due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs. Wet-lab experiments revealed that positive correlations partially remain in in vitro condition. INTERPRETATION: Our study brings new insights into the critical role of miRNA in gene regulation and the complex mechanisms underlying miRNA functions, and reveals both biological and clinical significance of miRNA-associated gene activation.