Non-Coding RNA

22 pages, 8888 KB

Open AccessReview

The Stiff Side of Cancer: How Matrix Mechanics Rewrites Non-Coding RNA Expression Programs

by Alma D. Campos-Parra, Jonathan Puente-Rivera, César López-Camarillo, Stephanie I. Nuñez-Olvera, Nereyda Hernández Nava, Gabriela Alvarado Macias and Macrina Beatriz Silva-Cázares

Non-Coding RNA 2026, 12(1), 7; https://doi.org/10.3390/ncrna12010007 - 18 Feb 2026

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Abstract

Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), [...] Read more.

Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), focal adhesion kinase (FAK) and the Hippo co-activators YAP1 and TAZ (WWTR1) promote proliferation, invasion, stemness and therapy resistance. Here, we synthesize evidence that quantitative changes in matrix stiffness remodel the miRNome and lncRNome in both tumor and stromal compartments, including extracellular vesicle cargo that reprograms metastatic niches. To address heterogeneity in experimental support, we classify mechanosensitive ncRNAs into studies directly validated by stiffness manipulation (e.g., tunable hydrogels/AFM) versus indirect associations based on mechanosensitive signaling, and we summarize physiological versus pathophysiological stiffness ranges across tissues discussed. We further review competing endogenous RNA (ceRNA) networks converging on mechanotransduction nodes and ECM remodeling enzymes, and discuss translational opportunities and challenges, including targeting mechanosensitive ncRNAs, combining ncRNA modulation with anti-stiffening strategies, delivery barriers in dense tumors, and the potential of circulating/exosomal ncRNAs as biomarkers. Overall, integrating ECM mechanics with ncRNA regulatory circuits provides a framework to identify feed-forward loops sustaining aggressive phenotypes in rigid microenvironments and highlights priorities for validation in physiologically relevant models. Full article

(This article belongs to the Section Long Non-Coding RNA)

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23 pages, 4501 KB

Open AccessArticle

Computational Analysis of Telomerase RNA Evolution in Caenorhabditis Species

by Christopher Klapproth, Franziska Reinhardt, Peter F. Stadler and Sven Findeiß

Non-Coding RNA 2026, 12(1), 6; https://doi.org/10.3390/ncrna12010006 - 11 Feb 2026

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Abstract

Background/Objectives: The telomerase RNA (TR) is an indispensable part of the telomerase protein complex responsible for telomere elongation in most eukaryotic species. Although the telomere terminal repeat sequence (TTAGGC)_n in Caenorhabditis elegans has been known for years, a telomerase RNA gene was [...] Read more.

Background/Objectives: The telomerase RNA (TR) is an indispensable part of the telomerase protein complex responsible for telomere elongation in most eukaryotic species. Although the telomere terminal repeat sequence (TTAGGC)_n in Caenorhabditis elegans has been known for years, a telomerase RNA gene was not identified in the entire phylum of Nematoda until recently. Methods: In this exploratory study, we employ a combination of different approaches to identify likely telomerase RNA candidates among putative non-coding transcripts. Results: A detailed analysis of our prime candidate shows compelling evidence that it encodes the missing RNA element of the telomerase complex, which is notably located in an intron of the coding gene nmy-2. Using nmy-2 homologs in other nematodes as anchors, we annotate the conserved TR gene in 21 Caenorhabditis species. We furthermore show that the intronic localization of the TR gene is conserved in two distinct branching groups of the Caenorhabditis phylogeny and demonstrate that this property likely emerged from a single point of origin. Conclusions: While the intronic TR represents a very interesting evolutionary adaption that seems to have been successful in the Elegans and Japonica groups, the question regarding the macroscopic nematode TR evolution remains. Full article

(This article belongs to the Section Evolution of Non-Coding RNA)

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24 pages, 3371 KB

Open AccessArticle

Extracellular Small RNAs in Human Milk: Molecular Profiles, Stability and Fragment-Specific Responses in Cell-Based Assays

by Clara Claus, Carla Borini Etichetti, Bruno Costa, Julieta B. Grosso, Juan Pablo Tosar, Uciel Chorostecki and Silvana V. Spinelli

Non-Coding RNA 2026, 12(1), 5; https://doi.org/10.3390/ncrna12010005 - 9 Feb 2026

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Abstract

Background/Objectives: Human milk is a complex biological fluid containing not only macro- and micronutrients but also diverse bioactive molecules, including extracellular RNAs. Although RNA has been detected in milk for decades, only a subset of RNA species has been characterized in detail, and [...] Read more.

Background/Objectives: Human milk is a complex biological fluid containing not only macro- and micronutrients but also diverse bioactive molecules, including extracellular RNAs. Although RNA has been detected in milk for decades, only a subset of RNA species has been characterized in detail, and abundant families such as tRNA-, yRNA-, and rRNA-derived fragments remain underexplored. This study aimed to define the composition, fragmentation patterns, stability, and exploratory functional activity of these highly abundant RNAs in human milk. Methods: We performed small RNA sequencing on skim milk samples and analyzed the resulting profiles in comparison with publicly available milk and biofluid datasets. RNA stability assays, Northern blotting, and RT-qPCR were conducted to validate RNA abundance and degradation kinetics. Extracellular vesicles (EVs) and non-vesicular fractions were analyzed to determine the subcellular distribution of RNA species. Exploratory functional assays using synthetic RNA fragments were carried out to assess their ability to modulate cellular responses in vitro. Results: Human milk was found to be highly enriched in small RNA fragments derived from tRNA, yRNA, and rRNA, dominated by a limited set of discrete sequences. These profiles were highly reproducible across independent datasets and distinct biofluids. Orthologal validation assays confirmed their abundance and stability, with RNA levels exceeding those of serum by over two orders of magnitude. Full-length transcripts were enriched in EVs, whereas shorter fragments predominated in the non-vesicular fraction. Synthetic milk-derived exRNAs showed detectable pro-survival activity under stress conditions in vitro. Conclusions: This study reveals that human milk carries a limited set of highly abundant stable sRNA molecules, primarily derived from tRNAs, yRNAs, and rRNAs. These findings provide new insights into the RNA cargo of human milk and offer preliminary evidence that selected sRNA fragments can modulate cellular stress responses in in vitro models. Full article

(This article belongs to the Section Small Non-Coding RNA)

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24 pages, 2774 KB

Open AccessReview

Mechanisms at the Intersection of lncRNA and m6A Biology

by Samuel J. Gonzalez, Edgardo Linares, Allison M. Porman Swain and Aaron M. Johnson

Non-Coding RNA 2026, 12(1), 4; https://doi.org/10.3390/ncrna12010004 - 31 Jan 2026

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Abstract

This review provides a thorough survey of long noncoding RNAs that bear the RNA modification N6-methyladenosine (m6A) and current work to understand the resulting mechanistic and biological consequences. We give an overview of lncRNA and m6A biology first, describing the writers, erasers, and [...] Read more.

This review provides a thorough survey of long noncoding RNAs that bear the RNA modification N6-methyladenosine (m6A) and current work to understand the resulting mechanistic and biological consequences. We give an overview of lncRNA and m6A biology first, describing the writers, erasers, and readers of m6A and their targeting of lncRNAs. Next, we give an in-depth review of the field of nuclear lncRNAs that regulate chromatin and their regulation via m6A. We then describe the growing appreciation of liquid–liquid phase separation properties in lncRNA and m6A biology. Finally, we cover examples of cytoplasmic lncRNAs regulated by m6A. Overall, this review aims to emphasize how epitranscriptomics influences noncoding RNA mechanisms to provide additional layers of regulation, integrated into downstream biological processes. Full article

(This article belongs to the Section Long Non-Coding RNA)

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16 pages, 3102 KB

Open AccessArticle

Hypercholesterolemia Impairs the Expression of Angiogenic MicroRNAs in Extracellular Vesicles Within Ischemic Skeletal Muscles

by Nozha Raguema, Sylvie Dussault, Kevin Sawaya, Michel Desjarlais, Eric Boilard, Sylvain Chemtob and Alain Rivard

Non-Coding RNA 2026, 12(1), 3; https://doi.org/10.3390/ncrna12010003 - 26 Jan 2026

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Abstract

Background/Objectives: In severe peripheral artery disease (PAD) with limb ischemia, hypercholesterolemia (HC) is associated with impaired neovascularization. Extracellular vesicles (EVs) are present within ischemic muscles, and they contain microRNAs (miRs) involved in several biological functions, including angiogenesis and neovascularization. Methods: We [...] Read more.

Background/Objectives: In severe peripheral artery disease (PAD) with limb ischemia, hypercholesterolemia (HC) is associated with impaired neovascularization. Extracellular vesicles (EVs) are present within ischemic muscles, and they contain microRNAs (miRs) involved in several biological functions, including angiogenesis and neovascularization. Methods: We used a mouse model of PAD and compared the response to hindlimb ischemia in hypercholesterolemic ApoE^−/− vs. normocholesterolemic mice. Next-generation sequencing (NGS) was used to perform full miR expression profiling in ischemic skeletal muscles and in EVs of varying sizes—large EVs (lEVs) and small EVs (sEVs)—within these muscles. Results: We identified several miRs with potential pro-angiogenic effects (angiomiRs) that are reduced by HC in lEVs (Let-7b-5p, miR-151-3p, Let-7c-5p) or sEVs (miR-21a-5p, miR-196b-5p, miR-340-5p). As proof of principle, we showed that the overexpression of Let-7b-5p in lEVs, or miR-21a-5p in sEVs, can significantly increase the angiogenic capacity of these EVs in vitro. HC also impaired the enrichment of specific angiomiRs in lEVs (miR-100-5p), sEVs (miR-142a-3p), or in both lEVs and sEVs (miR-146b-5p). In silico approaches, including the prediction of miR targets, pathway unions, and gene unions, identified the resulting predictive effects of HC-modulated miRs in EVs on processes with key roles in the modulation of angiogenesis and neovascularization, such as the regulation of the actin cytoskeleton and focal adhesion and the HIF-1, MAPK, AMPK, and PI3K-Akt signaling pathways. Conclusions: Our results constitute an important first step towards the identification of specific miRs that could be targeted to improve EV angiogenic function in hypercholesterolemic conditions and reduce tissue ischemia in patients with severe PAD. Full article

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21 pages, 652 KB

Open AccessReview

The Role of microRNAs as Potential Biomarkers in Diffuse Large B-Cell Lymphoma

by Eirini Panteli, Epameinondas Koumpis, Vasileios Georgoulis, Georgios Petros Barakos, Evangelos Kolettas, Panagiotis Kanavaros, Alexandra Papoudou-Bai and Eleftheria Hatzimichael

Non-Coding RNA 2026, 12(1), 2; https://doi.org/10.3390/ncrna12010002 - 7 Jan 2026

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma (NHL). While novel therapies such as rituximab and polatuzumab vedotin have led to improved outcomes, approximately 35% of patients eventually develop relapsed or refractory disease. MicroRNAs (miRNAs), [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma (NHL). While novel therapies such as rituximab and polatuzumab vedotin have led to improved outcomes, approximately 35% of patients eventually develop relapsed or refractory disease. MicroRNAs (miRNAs), a class of endogenous single-stranded RNAs approximately 22 nucleotides in length, play a pivotal role in the regulation of gene expression at the post-transcriptional level through interactions with complementary target RNAs and contribute significantly to the development, progression, and treatment response of DLBCL. Oncogenic miRNAs, such as miR-155, miR-21, and the miR-17–92 cluster, promote proliferation, survival, immune evasion, and therapy resistance by modulating pathways including PI3K/AKT, NF-κB, and MYC. Conversely, tumor-suppressive miRNAs such as miR-34a, miR-144, miR-181a, and miR-124-3p inhibit oncogene activity and enhance apoptosis, with their loss often associated with adverse outcomes. Among these, miR-155 and miR-21 are particularly well studied, playing central roles in both tumor progression and remodeling of the tumor microenvironment. This review summarizes current evidence on the biological and clinical relevance of miRNAs in DLBCL, emphasizing their diagnostic and prognostic potential. Full article

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18 pages, 5746 KB

Open AccessArticle

Functional and Molecular Characterization of Extracellular Vesicles Enriched in Exosomes Released by Bone Marrow Mesenchymal Stromal Cells Exposed to IFNγ in Combination with Autophagy Modulators Tamoxifen or Chloroquine

by Vladimir Beljanski, Maria J. Moreno Hollweg, Renee Potens, Tanner Blaylock, Andres B. Irausquin, Nikhila Paleati and Lubov Nathanson

Non-Coding RNA 2026, 12(1), 1; https://doi.org/10.3390/ncrna12010001 - 24 Dec 2025

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Abstract

Background/Objectives: Bone marrow mesenchymal stromal cells (MSCs) are therapeutic cells that adopt an immunomodulatory phenotype when exposed to pro-inflammatory cytokines. Recent research efforts uncovered that many therapeutic benefits of MSCs can be attributed to the secretion of extracellular vesicles (EVs) such as [...] Read more.

Background/Objectives: Bone marrow mesenchymal stromal cells (MSCs) are therapeutic cells that adopt an immunomodulatory phenotype when exposed to pro-inflammatory cytokines. Recent research efforts uncovered that many therapeutic benefits of MSCs can be attributed to the secretion of extracellular vesicles (EVs) such as exosomes, small membrane vesicles of endocytic origin present in the cellular secretome. EVs’ formation and release are impacted by the autophagy pathway, which recycles proteins and organelles via lysosomal degradation. Methods: To evaluate how modulation of autophagy affects properties of MSC EVs enriched in exosomes under pro-inflammatory conditions, we treated the cells with either tamoxifen (TX) or chloroquine (CQ), two drugs known to stimulate or inhibit autophagy, respectively, together with IFNγ. MSC EVs enriched in exosomes were then purified from serum-free media, and their immunoregulatory properties were evaluated ex vivo using activated CD4 T cells; small RNA sequencing was also conducted to determine EVs’ microRNA content. Results: Our data indicate that MSCs treated with CQ + IFNγ yield EVs that possess somewhat higher capacity to decrease T cell proliferation compared to other EVs. Small RNA sequencing revealed that, although similar microRNAs were found in EVs isolated from all treated cells, the treatments exerted more effect on the levels of multiple microRNAs that are known to regulate either cancer or inflammation-related biological pathways in target cells. Conclusions: Overall, we conclude that the co-treatment of MSCs with TX or CQ in the presence of pro-inflammatory cytokine IFNγ has the potential to modulate microRNA content of EVs, potentially affecting biological properties of such EVs and their effect on target cells. Full article

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Non-Coding RNA, Volume 12, Issue 1 (February 2026) – 7 articles

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