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

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. Electronic supplementary material The online version of this article (10.1186/s12864-019-5850-7) contains supplementary material, which is available to authorized users.

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives

“…Twelve lncRNAs involved in one of the modules were found to be closely related to the formation of CAFs. The authors carried out siRNA knockdown experiments and observed that the transformation of NFs to CAFs was decreased, confirming this correlation [187]. In another study, a lncRNA significantly upregulated in CAFs was identified from oral squamous cell carcinoma (OSCC) by RNA sequencing; this lncRNA was found to promote the transformation of NFs to CAFs and affect the proliferation of cancer cells by increasing the IL-33 level [188].…”

Transcriptomic meta-analysis reveals unannotated long non-coding RNAs related to the immune response in sheep

“…In the case of the co-expression analyses, following the principle of guilt-by-association ( Wolfe et al, 2005 ), association with the immune response was assigned via correlation to a group of co-expressed genes. This approach has been widely used for the functional profiling of lncRNAs by several studies ( Walters et al, 2019 ; de Goede et al, 2021 ). In addition, one of the datasets included in this study has already been analysed in this way to specifically search for candidate lncRNAs during an helminth infection ( Chitneedi et al, 2021 ).…”

The Interaction Between Long Non-Coding RNAs and Cancer-Associated Fibroblasts in Lung Cancer

“…Twelve lncRNAs in one of these were associated with cancer fibroblasts activation. Differentiation of quiescent fibroblasts into cancer-associated phenotypes was reduced by siRNA knockdown experiment (Walters et al, 2019). Snail1 2016).…”

“…Twelve lncRNAs in one of these were associated with cancer fibroblasts activation. Differentiation of quiescent fibroblasts into cancer-associated phenotypes was reduced by siRNA knockdown experiment ( Walters et al, 2019 ). Snail1 activates cancer-associated fibroblasts (CAF), which require signals from tumor cells such as TGF-β ( Alba-Castellón et al, 2016 ).…”