LncRNA-encoded peptides in cancer

Abstract

Long non-coding RNAs (lncRNAs), once considered transcriptional noise, have emerged as critical regulators of gene expression and key players in cancer biology. Recent breakthroughs have revealed that certain lncRNAs can encode small open reading frame (sORF)-derived peptides, which are now understood to contribute to the pathogenesis of various cancers. This review synthesizes current knowledge on the detection, functional roles, and clinical implications of lncRNA-encoded peptides in cancer. We discuss technological advancements in the detection and validation of sORFs, including ribosome profiling and mass spectrometry, which have facilitated the discovery of these peptides. The functional roles of lncRNA-encoded peptides in cancer processes such as gene transcription, translation regulation, signal transduction, and metabolic reprogramming are explored in various types of cancer. The clinical potential of these peptides is highlighted, with a focus on their utility as diagnostic biomarkers, prognostic indicators, and therapeutic targets. The challenges and future directions in translating these findings into clinical practice are also discussed, including the need for large-scale validation, development of sensitive detection methods, and optimization of peptide stability and delivery.

Keywords: Application; Cancer; Long non-coding RNA; Peptide; Small open reading frame.

Fig. 1

Detection methods for the coding potential of lncRNAs. A Prediction of short open reading frames (ORFs) within lncRNAs. B Sucrose density gradient separation to detect ribosome enrichment on lncRNAs. C Detection of GFP translation using a GFP fusion with a mutated start codon within a lncRNA ORF. D Integration of a tag at the lncRNA ORF site using gene editing technology to assess the expression of the tagged protein. LHA, left homologous arm; RHA, right homologous arm. E Detection of intracellular lncRNA-encoded peptides using antibodies raised against synthetic peptides. F Mass spectrometry identification of peptide expression. Image created with BioRender.com

Fig. 2

The role of lncRNA-encoded peptides in colorectal cancer (CRC). A The peptide HOXB-AS3 encoded by LncRNA HOXB-AS3 interacts with hnRNP A1 to affect PKM mRNA splicing, inhibiting CRC growth and metastasis. B The peptide SRSP encoded by LncRNA LOC90024 interacts with SRSF3 to influence splicing of SP4 mRNA, promoting CRC growth and metastasis. C The peptide RBRP encoded by LINC00266-1 interacts with IGF2BP1 to maintain c-Myc mRNA stability, promoting CRC growth and metastasis. D The peptide ASAP encoded by LINC00467 enhances ATP synthase activity and mitochondrial oxygen consumption by interacting with ATP5A and ATP5C, promoting CRC growth. E The peptide pep-AP encoded by Lnc-AP interacts with TALDO1 to attenuate the pentose phosphate pathway (PPP), inducing apoptosis and drug sensitivity in colorectal cancer cells. F The peptide BVES-AS1-201-50aa encoded by LncRNA BVES-AS1 activates the Src/mTOR signaling pathway, promoting CRC proliferation, migration, and invasion. G The peptide MBOP encoded by LINC01234 interacts with MEK1 to regulate the MEK1/pERK/MMP2/MMP9 axis, promoting CRC proliferation and metastasis. H The peptide FORCP encoded by LINC00675 induces apoptosis and inhibits cell proliferation in colorectal cancer cells under endoplasmic reticulum stress. Image created with BioRender.com

Fig. 3

The role of lncRNA-encoded peptides in breast cancer. A The peptide MRP encoded by LncRNA LY6E-DT regulates EGFR mRNA stability and translation by interacting with HNRNPC, promoting breast cancer metastasis. B The peptide LINC00511-133aa encoded by LINC00511 facilitates β-catenin nuclear translocation to activate the transcription of Bax, c-Myc, and CyclinD1, promoting invasiveness and stem-like properties of breast cancer. C The peptide HCP5-132aa encoded by LncRNA HCP5 inhibits autophagy and ferroptosis to promote breast cancer proliferation and migration. D The peptide ASRPS encoded by LINC00908 inhibits STAT3 phosphorylation, leading to the suppression of VEGF transcription and thus inhibiting tumor metastasis and angiogenesis. E The peptide CIP2A-BP encoded by LINC00665 competes with PP2A for binding to CIP2A, reducing AKT phosphorylation to inhibit the PI3K/AKT/NFκB pathway, leading to the downregulation of MMP2, MMP9, and Snail, thus inhibiting breast cancer invasion and metastasis. F The peptide MAGI2-AS3-ORF5 encoded by LncRNA MAGI2-AS3 interacts with extracellular matrix proteins to inhibit breast cancer cell proliferation and migration. Image created with BioRender.com

Fig. 4

The role of lncRNA-encoded peptides in liver cancer. A The peptide HBVPTPAP encoded by LncRNA HBVPTPAP promotes membrane localization of PILRA by interacting with it, activating the JAK/STAT signaling pathway to induce apoptosis and inhibit liver cancer development. B The peptide SMIM30 encoded by LINC00998 activates the MAPK signaling pathway and regulates the G1/S phase transition to promote liver cancer proliferation and metastasis. C The peptide PINT87aa encoded by LINC-PINT interacts with FOXM1 to inhibit PHB2 transcription, inducing cellular senescence and suppressing liver cancer growth. D The peptide C20orf204-189AA encoded by LINC00176 promotes liver cancer cell proliferation by stabilizing Nucleolin and enhancing rRNA transcription. E The peptide CIP2A-BP encoded by LINC00665 promotes liver cancer growth and metastasis. F The peptide Linc013026-68aa encoded by LINC013026 enhances the in vitro proliferation of HCC cells. Image created with BioRender.com

Fig. 5

The role of lncRNA-encoded peptides in lung cancer. A The peptide ATMLP encoded by lncRNA AFAP1-AS1 disrupts autolysosome formation by interacting with NIPSNAP1, hindering its transport, leading to lung cancer development and progression. B The peptide encoded by lncRNA DLX6-AS1 enhances the proliferation, migration, and invasion of NSCLC cells by activating the Wnt/β-catenin signaling pathway. C The peptide UBAP1-AST6 encoded by an LncRNA promotes the proliferation of lung cancer cells in vitro. Image created with BioRender.com

Fig. 6

The role of lncRNA-encoded peptides in esophageal cancer. A The peptide Pep-KDM4A-AS1 encoded by LincKDM4A-AS1 inhibits the proliferation and migration of esophageal cancer cells by regulating intracellular redox processes and fatty acid metabolism. B The peptide Pep‐LINC01116 encoded by LINC01116 reduces the viability of ESCC cells and inhibits their migration. C The peptide YY1BM encoded by LINC00278 promotes apoptosis in esophageal cancer cells by disrupting the binding of YY1 and AR, leading to reduced eEF2K expression. Image created with BioRender.com

Fig. 7

The role of lncRNA-encoded peptides in pancreatic and renal cancers. A The peptide RASON encoded by LINC00673 promotes the growth of pancreatic cancer by stabilizing KRASG12D/V in an active GTP-bound state through interaction with KRASG12D/V. B The peptide SMIM26 encoded by LINC00493 inhibits the proliferation and migration of renal cell carcinoma by enhancing mitochondrial localization of AGK, thereby inhibiting AGK-mediated AKT phosphorylation. C The peptide MIAC encoded by LncRNA AC025154.2 inhibits the proliferation and migration of renal cell carcinoma by interacting with AQP2 to suppress the expression of EREG/EGFR. Image created with BioRender.com

Fig. 8

The role of lncRNA-encoded peptides in ovarian and glioblastoma cancers. A The peptide DDUP encoded by LncRNA CTBP1-DT enhances DNA damage repair and cisplatin resistance in ovarian cancer cells by interacting with H2A.X and RAD18. B The peptide NBASP encoded by LncRNA increases the degradation of FABP5, leading to the inactivation of the MAPK pathway and inhibiting the proliferation and migration of glioblastoma cells. C The peptide sPEP1 encoded by LncRNA HNF4A-AS1 promotes the transcriptional upregulation of hepatocyte-related genes by enhancing the interaction with SMAD4, leading to the occurrence and metastasis of glioblastoma. Image created with BioRender.com

Fig. 9

lncRNA-encoded peptides identified in various human tumor types. NB, Neuroblastoma; BC, Breast cancer; PDAC, Pancreatic ductal adenocarcinoma; LIHC, Liver cancer; OS, Osteosarcoma; OSCC, Oral squamous cell carcinoma; ESCC, Esophageal squamous cell carcinoma; LC, Lung cancer; RCC, Renal cell carcinoma; CRC, Colorectal cancer; OV, Ovarian cancer. Image created with BioRender.com

Fig. 10

Potential applications of lncRNA-encoded peptides. LncRNA-encoded peptides can be utilized in various aspects of oncology, including cancer diagnosis, prognosis, therapeutic target, drug development, immune regulation, and regenerative medicine. SEP, sORF-encoded peptide. Image created with BioRender.com