GlycoRNAs have emerged as a new area of study in cancer, cardiovascular,  neurological, immune, and respiratory diseases, opening up new avenues into novel biomarker and therapeutic applications.
 

Breast Cancer

Surface glycoRNAs are inversely related with tumor malignancy and metastasis, i.e. breast non-cancer cells (MCF-10A) have the highest glycoRNA levels, followed by breast cancer cells (MCF-7), while breast metastatic cancer cells (MDA-MB-231) exhibits the lowest levels [1] (Fig.1). The inverse relationship suggests that these glycoRNAs could be used as biomarkers of breast cancer progression and metastasis.

Fig.1 Heatmap of glycoRNA levels on breast cancer cells at different malignancy and metastasis stages as measured by sialic acid aptamer and RNA in situ hybridization-mediated proximity ligation assay (ARPLA).
 

Pancreatic Cancer

Specific glycosylated microRNAs have been identified as regulators of pancreatic cancer cell growth and proliferation [2]. For instance, glycosylated miR-103a-3p, miR-122-5p, and miR-4492 can regulate pancreatic cancer cell growth and proliferation through the PI3K-Akt pathway [2-3](Fig.2). Furthermore, by affecting the expression of glycol-miRNAs (e.g. hsa-miR-21-5p), β-1,4-galactosyltransferase 1 (B4GALT1) can suppress the cell cycle and promote apoptosis in MIA PaCa-2 pancreatic cancer cells. Thus, B4GALT1 could be the glycosylation enzyme for the miRNAs [3].

Fig.2 Glyco-miRNAs differentially expressed pancreatic cancer cells are enriched in the regulation of oncogenic signaling pathways in Gene Ontology (A) and KEGG pathway (B) analysis [3].
 

Cardiovascular Diseases

Y-RNAs, a class of highly conserved small noncoding RNAs (~110 nt), are major targets for glycosylation [6-7]. They play a precedential role in immunoregulation. Interestingly, Y-RNAs represent > 60% of the circulating RNAs in humans and their levels correlate positively with the progression of atherosclerosis, a major risk factor for ischemic stroke [4-5]. Specifically, Y-RNA fragments activate macrophages and promote inflammation during atherosclerosis [5]. These observations suggest that glycosylated Y-RNAs could be risk factors and biomarkers for cardiovascular diseases.
 

Stroke

GlycoRNAs are hypothesized to modulate inflammatory responses in the ischemic brain [10](Fig.3). Similar to neuronal glycoproteins, glycoRNAs potentially act as ligands for microglial Siglec-11 receptors and polarize them to the anti-inflammatory phenotype by reducing the expression of cytokines like IL-1b and nitric oxide generating NOS2. Targeting glycoRNA pathways could be a promising approach for stroke treatment and recovery.

Fig.3 Putative role of glycoRNAs after stroke. GlycoRNAs on the neuronal cell surface act as a ligand for microglial Siglec-11 receptors to reduce IL-1b cytokine and nitric oxide production, initiating anti-inflammatory cascade after ischemic stroke [10].
 

Immunomodulation

GlycoRNAs have been found to interact with immune cell receptors, specifically the members of sialic acid-binding immunoglobulin-like lectin (Siglec) receptor family [6]. Neutrophil surface glycoRNAs are essential for regulating neutrophil adhesion to endothelial cells, facilitating transendothelial migration, and controlling neutrophil recruitment [8](Fig.4). Furthermore, lectin Selp, in contrast to Sele, can identify at least a subset of neutrophil glycoRNAs. Thus, glycoRNA ligands for Selp may confer unique ligand specificity, even among the highly similar lectin proteins [8]. GlycoRNAs on immune cells could have broad implications for various immune-related conditions and autoimmune diseases.

Fig.4 GlycoRNAs serve as a ligand for P-selectin to control neutrophil recruitment.
 

Alveolar Epithelial Functions

GlycoRNA represents a novel component in alveolar epithelial glycocalyx to regulate epithelial barrier function or influence influenza A virus infection [9]. The identified function of glycoRNA as a ligand for sialic acid-binding immunoglobulin-like lectins (siglecs) 11 and 14 on immune cells - including macrophages, monocytes, and neutrophils - could influence the immune cell interactions in the context of inflammatory lung diseases [6]. Additionally, glycoRNAs present on the surface of alveolar epithelial cells may engage with lung collectins, such as surfactant proteins A and D, further contributing to respiratory immune responses [9]. Consequently, analyzing the presence of shed glycoRNAs in bronchoalveolar lavage fluid may provide a valuable biomarker for assessing epithelial damage and disruption.
 

Related Service

GlycoRNA Array Service
 

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What Are GlycoRNAs? 

How to Study GlycoRNAs?
 

References
1. Ma Y. et al (2024) "Spatial imaging of glycoRNA in single cells with ARPLA" Nat Biotechnol 42(4):608-616 [PMID:37217750]
2. Li, J. et al (2024) "O-Glycosylated RNA Identification and Site-specific Prediction by Solid-phase Chemoenzymatic TnORNA method and PONglyRNA tool" bioRxiv [doi: https://doi.org/10.1101/2024.06.18.599663]
3. Li J. et al (2023) "Novel Approach to Enriching Glycosylated RNAs: Specific Capture of GlycoRNAs via Solid-Phase Chemistry." Anal Chem 95(32):11969-11977 [PMID:37524653]
4. Driedonks TAP. and Nolte-'t Hoen ENM. (2018) "Circulating Y-RNAs in Extracellular Vesicles and Ribonucleoprotein Complexes; Implications for the Immune System." Front Immunol 9:3164 [PMID:30697216]
5. Hizir Z. et al (2017) "RNY (YRNA)-derived small RNAs regulate cell death and inflammation in monocytes/macrophages." Cell Death Dis 8(1):e2530 [PMID:28055017]
6. Flynn RA. et al (2021) "Small RNAs are modified with N-glycans and displayed on the surface of living cells." Cell 184(12):3109-3124.e22 [PMID:34004145]
7. Flynn, RA. et al (2019) "Mammalian Y RNAs are modified at discrete guanosine residues with N-glycans." bioRxiv [https://doi.org/10.1101/787614]
8. Zhang N. et al (2024) "Cell surface RNAs control neutrophil recruitment." Cell 187(4):846-860.e17 [PMID:38262409]
9. Abledu, JK. et al (2024) "Cell surface RNA expression modulates alveolar epithelial function." bioRxiv [https://doi.org/10.1101/2024.05.19.594844]
10.  Chokkalla AK. et al (2023) "Immunomodulatory role of glycoRNAs in the brain." J Cereb Blood Flow Metab 43(4):499-504 [PMID:36644904]

 

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