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Published on: May 30, 2025
Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and
Kevin Walters1, Radmir Sarsenov2, Wen Siong Too2
1School of Mathematics and Statistics, University of Sheffield, Sheffield, South Yorkshire, UK.
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.
Insights
This study reveals 16 long non-coding RNA (lncRNA) modules across 32 cancer types, uncovering their roles in cancer progression and function. These findings offer new hypotheses for lncRNA involvement in tumor development.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Long non-coding RNAs (lncRNAs) are critical regulators in cellular processes, yet their functions in diseases like cancer are largely unknown.
- Understanding lncRNA roles is essential for advancing cancer research and therapeutic strategies.
Purpose of the Study:
- To integrate gene expression profiles across 32 cancer types to functionally characterize human lncRNAs.
- To identify lncRNA modules associated with specific functions, disease relevance, and regulatory mechanisms.
Main Methods:
- A novel strategy was employed to integrate pan-cancer gene expression data.
- Human lncRNAs were clustered based on associations with protein-coding genes, yielding 16 distinct modules.
- Functional themes were identified through module analysis, including transcription regulation, immunological, extracellular, and neurological categories.
Main Results:
- 16 lncRNA modules were identified, falling into four functional themes: transcription regulation, immunological, extracellular, and neurological.
- Three extracellular matrix-associated modules highlighted lncRNA networks in tumor progression, including a 33-lncRNA signature for epithelial-mesenchymal transition induction.
- Stromal-specific modules revealed lncRNAs linked to tumor suppression and cancer-associated fibroblasts, with experimental validation for one signature member.
Conclusions:
- The study provides a comprehensive pan-cancer view of the lncRNA functional landscape.
- It serves as a valuable resource for generating novel hypotheses regarding lncRNA contributions to tumor progression.
- The identified lncRNA modules offer potential targets for future cancer research and therapeutic development.
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