Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and modular analysis of their protein-coding gene association networks
Document Type
Article
Publication Date
1-1-2019
Abstract
Background: Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes in diseases such as cancer, although the functions of most remain poorly understood. To address this, here we apply a novel strategy to integrate gene expression profiles across 32 cancer types, and cluster human lncRNAs based on their pan-cancer protein-coding gene associations. By doing so, we derive 16 lncRNA modules whose unique properties allow simultaneous inference of function, disease specificity and regulation for over 800 lncRNAs. Results: Remarkably, modules could be grouped into just four functional themes: transcription regulation, immunological, extracellular, and neurological, with module generation frequently driven by lncRNA tissue specificity. Notably, three modules associated with the extracellular matrix represented potential networks of lncRNAs regulating key events in tumour progression. These included a tumour-specific signature of 33 lncRNAs that may play a role in inducing epithelial-mesenchymal transition through modulation of TGFβ signalling, and two stromal-specific modules comprising 26 lncRNAs linked to a tumour suppressive microenvironment and 12 lncRNAs related to cancer-associated fibroblasts. One member of the 12-lncRNA signature was experimentally supported by siRNA knockdown, which resulted in attenuated differentiation of quiescent fibroblasts to a cancer-associated phenotype. Conclusions: Overall, the study provides a unique pan-cancer perspective on the lncRNA functional landscape, acting as a global source of novel hypotheses on lncRNA contribution to tumour progression. © 2019 The Author(s).
Keywords
Cancer, Epithelial-mesenchymal transition, Extracellular matrix, Functional profiling, Genes networks, lncRNA, Tumour microenvironment
Divisions
OralBiology
Funders
Yorkshire Cancer Research (YCR SHEND01/02),University of Malaya Research grant (RG456-12HTM)
Publication Title
BMC Genomics
Volume
20
Issue
1
Publisher
BioMed Central