Jul 2026· British Journal of Cancer· 1 citation· 45 references
Medicine
TL;DR
Tr-lncRNA-derived MPs represent a previously underexplored class of potentially functional molecules associated with cancer clinical annotation and may serve as biomarkers for disease progression.
Abstract
Background
Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Although traditionally considered non-coding, 21% of the ~190,000 annotated lncRNA transcripts contain poorly characterized open reading frames with unknown function.
Methods
We systematically identified lncRNAs encoding micropeptides (MPs) using integrated computational and experimental evidence. Expression profiles across 17 cancer types from The Cancer Genome Atlas (TCGA) were analyzed to identify cancer-associated and transitional lncRNAs (Tr-lncRNAs). Structural modeling using AlphaFold was further applied to predict folding.
Results
We identified 478 lncRNA genes encoding 1782 MPs (10-100 amino acids). These MPs exhibit distinct amino acid and dipeptide compositions and are enriched for specific 4-mer motifs compared with canonical proteins. A subset of lncRNAs, including TNN-AS1, PVT1, XIST, and SNHG family members, encode multiple MPs. Analysis across cancer stages identified 2399 Tr-lncRNAs, most of them were cancer type and stage specific. Among these, 314 highly confident MPs from 72 Tr-lncRNAs were further analyzed. Pan-cancer analysis suggested MP-like functions for Tr-lncRNAs such as LINC01234, HAND2-AS1, XIST, UCA1, and HOXA11-AS. While most MPs are predicted to be intrinsically disordered, 3D structural modeling revealed several MPs with stable folds, including ubiquitin-like and RNase H-like structures.
Conclusions
Tr-lncRNA-derived MPs represent a previously underexplored class of potentially functional molecules associated with cancer clinical annotation and may serve as biomarkers for disease progression.
Abstract Motivation Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Recent studies indicate that ∼20% of the ∼36 000 human lncRNA genes harbor small open reading frames (sORFs) capable of producing micropeptides (MPs), whose functions remain largely unknown. Whether these peptides contribute to the cancer immunopeptidome is largely unexplored. Results We systematically analyzed lncRNAs with strong experimental and computational evidence of MP-encoding potential (∼13% of the initial MP collection). Using The Cancer Genome Atlas (TCGA), we identified 2606 high-confidence lncRNA-derived MPs encoded by 647 genes across 16 cancer types. We then focused on 501 MPs from 124 lncRNA genes whose expression changes significantly across tumor stages and metastatic transitions, representing cancer transitional lncRNAs (Tr-lncRNAs). Dipeptide composition and conservation analyses showed that these MPs differ from a size-matched human coding proteome, supporting their potential as neoantigens. All possible 9-mer peptides were evaluated for predicted binding to prevalent European HLA class I alleles. Approximately 60% of Tr-lncRNA genes and 184 (37%) of derived peptides exhibited strong predicted HLA binding. Peptides from XIST, PCAT7, PVT1, HAND2-AS1 showed broad HLA coverage. Notably, TTN-AS1, encoded an MP (79 aa) generated 33 predicted distinct epitopes spanning all 27 HLA alleles. Our analysis identifies lncRNA-derived MPs as a previously underexplored source of potential cancer neoantigens, highlighting their promise as biomarkers and targets for immunotherapy. Availability Data, code and supplementary materials are available in https://doi.org/10.5281/zenodo.20167452 and GitHub: https://github.com/stavzok1/lncrna_peptide_analysis.
A mechanism wherein SChLAP1 modulates AR signaling to promote PCa growth and progression is suggested, suggesting its molecular mechanism and potential to be used as a therapeutic target or biomarker.
It is proposed that the upregulated lncRNA ENSG00000265613 may enhance malignancy by stabilizing the RNA target ENSG00000582008 in luminal A breast cancer, particularly given its established role in oncogenesis.
C. Guda, Sankarasubramanian Jagadesan, Avinash M. Veerappa· Methods in molecular biology· 0 citations
This computational study identifies several candidate lncRNAs associated with clinical outcomes in breast cancer, which should be interpreted as preliminary candidates, which require future validation and functional studies to determine their biological roles and evaluate their potential as prognostic biomarkers.
M. Acencio, Xin-Hui Wang, Flavia R. Rotea Mangone et al.· International Journal of Mol...· 0 citations
ENST00000615487.1 is a structurally stable lncRNA exhibiting context-dependent expression and localization patterns in CRC, suggesting a potential shift from nuclear transcriptional regulation toward cytoplasmic post-transcriptional functions during colorectal carcinogenesis.
Nataša Đokić, Anastasija Bubanja, Jelena Karanović et al.· Non-Coding RNA· 0 citations
INTRODUCTION
Despite the rapidly expanding catalog of long noncoding RNAs (lncRNAs), the functional roles of most remain poorly characterized in cancer. In triple-negative breast cancer (TNBC), an aggressive subtype with limited targeted treatment options, defining lncRNA-associated molecular mechanisms could uncover novel therapeutic vulnerabilities.
OBJECTIVES
This study aimed to systematically identify TNBC-enriched lncRNAs associated with cellular fitness, and drug response, and to functionally characterize prioritized lncRNA candidates with potential therapeutic relevance.
METHODS
We generated comprehensive lncRNA annotation by integrating GENCODE, BIGTranscriptome, and MiTranscriptome databases. CRISPR-Cas9 deletion screen targeting 1,029 TNBC-enriched lncRNAs was conducted. Functional validation included proliferation assays in 2D and 3D cultures, invasion assays using an organ-on-chip model, and transcriptomic and proteomic profiling following lncRNA knockdown. Candidate lncRNA-protein associations were assessed using proteomic array analysis. miRNA expression profiling, miRanda-based interaction prediction, and Ingenuity Pathway Analysis (IPA) were used to construct candidate competing endogenous RNA (ceRNA)-like regulatory networks and downstream signaling pathways.
RESULTS
Our CRISPR screen identified fourteen recurrent candidate lncRNA dependencies across both TNBC models, with TNBC Promoting LncRNA 1 (TPL1) emerging among the top candidates. ASO-mediated TPL1 suppression significantly reduced TNBC cell proliferation, clonogenic growth, three-dimensional growth, and invasive capacity. TPL1 was significantly overexpressed in TNBC tissues, particularly within the basal-like immune-suppressed (BLIS) subtype. RNA-FISH analysis showed nuclear/perinuclear and cytoplasmic TPL1 localization. Transcriptomic and proteomic analyses revealed suppression of pathways related to extracellular matrix-receptor interaction, focal adhesion, cell migration, and PI3K-Akt signaling following TPL1 knockdown. Proteomic array, RBPsuite, TLC-CLIP, miRNA profiling, and transcriptomic integration supported candidate protein-associated and ceRNA-like regulatory mechanisms involving TPL1.
CONCLUSION
This study identifies TPL1 as a functionally relevant lncRNA associated with TNBC growth, invasion, and molecular regulatory programs. These findings support TPL1 as a candidate RNA-targetable vulnerability in TNBC and provide a framework for further mechanistic and translational investigation.
R. Elango, S. Ramnarayanan, Radhakrishnan Vishnubalaji et al.· Journal of Advanced Research· 0 citations