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Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 July 2025) | Viewed by 10796

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Dr. Simone Anfossi

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Guest Editor

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: molecular and cell immunology; non-coding RNA; extracellular vesicles; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Dr. Linda Fabris

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Guest Editor

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: ncRNAs; ultra-conserved DNA regions

Special Issue Information

Dear Colleagues,

Cancer is a complex genetic disorder where the alteration of the expression of the genes drives functional changes in the biology of cells, leading to the development of cancer. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a relevant role in the regulation of gene expression. The aberrant expression of ncRNAs is frequently found in cancer cells, contributing to cancer development and progression. Aside from their localization inside cells, ncRNAs can also be found in the extracellular space as an intercellular messenger. Indeed, ncRNAs can be shuttled among the cells within the tumor microenvironment and even distant organs in a cell-free fashion, either encapsulated in extracellular vesicles (EVs) or complexed with lipoprotein. The delivery of ncRNAs can regulate recipient cells' gene expression and biological functions. The bidirectional communication between cancer cells and normal surrounding cells (immune, endothelial, epithelial, and stromal cells) is essential in regulating cancer progression. The study of the functional role of cellular and extracellular ncRNAs will help gain further insights into understanding the molecular mechanisms regulating cancer initiation and progression, as well as identifying new potential targets for novel cancer therapy.

Dr. Simone Anfossi
Dr. Linda Fabris
Guest Editors

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Keywords

ncRNAs
gene expression regulation
biological functions
extracellular vesicles
intercellular communication
cancer progression
tumor microenvironment

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Published Papers (5 papers)

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Research

32 pages, 3747 KB

Open AccessArticle

Interplay Between Dysregulated Immune System and the Footprints of Blood-Borne miRNAs in Treatment Naive Crohn’s Disease and Ulcerative Colitis Patients

by Emese Szilagyi-Tolnai, Anna Anita Szilagyi-Racz, Orsolya Kadenczki, Andras Balajthy, Peter David, Gabor Fidler, Peter Fauszt, Kristof Gal, Judit Remenyik, Karoly Palatka, Gyorgy Panyi, Melinda Paholcsek and Gabor Tajti

Int. J. Mol. Sci. 2025, 26(24), 12042; https://doi.org/10.3390/ijms262412042 - 15 Dec 2025

Viewed by 774

Abstract

Dysregulated T-cell-mediated immune responses are a hallmark of inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). MicroRNAs (miRNAs) regulate various biological processes and play a significant role in the pathophysiology of numerous diseases. In this study, we aim to clarify the relationship between dysregulated immune response and altered miRNA signatures in patients with IBD. Our goal is to identify differentially expressed miRNAs that could potentially serve as diagnostic markers to differentiate between CD and UC. To quantify circulating miRNAs, we employed small RNA sequencing. To describe immune dysregulation, we determined the levels of circulating T-cell-related cytokines and the distribution of T-cell subpopulations in both circulation and in tissue samples. Our analysis revealed that 14 miRNAs exhibited significant expression differences between IBD patients and control subjects. These miRNAs may also implicate pathways associated with colitis-related colorectal carcinogenesis, suggesting their value in early risk assessment. Furthermore, we found that five miRNAs demonstrated a strong ability to discriminate between CD and UC patients. Additionally, levels of IL-22 and IFN-γ were significantly elevated in individuals with IBD. Notably, miRNA levels showed strong correlations with cytokine levels and T-cell subset distribution in both blood and tissue samples, exhibiting disease-specific patterns. In conclusion, we identified differentially expressed miRNAs in IBD patient groups, and a subset of these miRNAs might exhibit diagnostic potential to distinguish between CD and UC. Analyzing miRNAs in the blood of IBD patients may provide valuable insights into the underlying immune dysfunction. Full article

(This article belongs to the Special Issue Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells)

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21 pages, 2778 KB

Open AccessArticle

Analysis of the Circulating miRNome Expression Profile in Saliva Samples After Neoadjuvant Chemoradiotherapy in a Rectal Cancer Study Population Using Next-Generation Sequencing

by Kristóf Gál, Péter Dávid, Melinda Paholcsek, Márton Barabás, Endre Szilágyi, Krisztina Balogh, Dóra Solymosi, Szidónia Miklós, Johanna Mikáczó, Krisztina Trási, Emese Csiki, Mihály Simon, Péter Fauszt, Szilárd Póliska, Judit Remenyik, Árpád Kovács and Emese Szilágyi-Tolnai

Int. J. Mol. Sci. 2025, 26(21), 10506; https://doi.org/10.3390/ijms262110506 - 29 Oct 2025

Viewed by 1295

Abstract

Dysregulated microRNAs (miRNAs) have been implicated in the pathogenesis and progression of rectal adenocarcinoma. In this study, we aimed to identify miRNA alterations associated with the efficacy of neoadjuvant chemoradiotherapy in rectal cancer patients. High-throughput small RNA sequencing was performed to assess salivary miRNA expression profiles in 31 participants (11 rectal adenocarcinoma patients and 20 healthy volunteers). Paired saliva samples were collected from patients before and after chemoradiation. Tumor regression was classified according to the modified Ryan scheme into responders (tumor regression grade [TRG] 1–2, n = 10) and nonresponders (TRG3, n = 1). Bioinformatic integration of small non-coding RNA data revealed 37 miRNAs with distinct expression differences between patients and healthy controls. Furthermore, seven miRNAs showed significant alterations in response to radiotherapy. Among these, five candidates (hsa-miR-378a-3p, hsa-miR-203a-3p, hsa-miR-200a-5p, hsa-miR-361-5p, and hsa-miR-107) were successfully validated by RT-qPCR, displaying significantly increased salivary expression levels post-radiation compared with the pre-radiation samples (p < 0.05). Notably, hsa-miR-203a-3p, hsa-miR-200a-5p, and hsa-miR-361-5p demonstrated excellent discriminatory power for tumor regression grade (AUC > 0.7). Our findings support the involvement of specific salivary miRNAs in rectal adenocarcinoma tumor regression and highlight their potential as non-invasive biomarkers to evaluate treatment response following neoadjuvant chemoradiotherapy. Full article

(This article belongs to the Special Issue Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells)

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13 pages, 1148 KB

Open AccessArticle

Novel lncRNA UGGT1-AS1 Regulates UGGT1 Expression in Breast Cancer Cell Line

by Klaudia Samorowska, Elżbieta Wanowska and Michał Wojciech Szcześniak

Int. J. Mol. Sci. 2025, 26(11), 5108; https://doi.org/10.3390/ijms26115108 - 26 May 2025

Viewed by 1247

Abstract

Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides long that do not encode proteins. Although many lncRNAs remain uncharacterized, they are known to play diverse regulatory roles in gene expression. A group of lncRNAs called natural antisense transcripts can form double-stranded structures with their sense partners due to sequence complementarity. These duplexes can become substrates for A-to-I RNA editing, an epitranscriptomic modification mediated by ADAR enzymes. RNA editing is known to influence transcript splicing, affect the resulting gene expression product or alter RNA stability, all of which can impact cancer cell biology. Here, we show a novel natural antisense transcript, UGGT1-AS1, that we have identified and characterized in terms of its cellular localization and sense partner interactions. Furthermore, we demonstrate that UGGT1-AS1 affects cell proliferation and regulates the stability of the UGGT1 sense transcript. Finally, using publicly available RNA sequencing data, we identify A-to-I RNA editing events in the protein-coding gene UGGT1 and further confirm them by RT-PCR and Sanger sequencing in MCF7 cell lines. We hypothesize that UGGT1-AS1 may act as a triggering factor for the A-to-I RNA editing process in its sense partner. Our findings highlight the regulatory role of UGGT1-AS1 and suggest its involvement in RNA editing and cancer biology. Full article

(This article belongs to the Special Issue Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells)

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19 pages, 6122 KB

Open AccessArticle

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels

by Krishna M. Shivakumar, Gowthami Mahendran and Jessica A. Brown

Int. J. Mol. Sci. 2024, 25(3), 1630; https://doi.org/10.3390/ijms25031630 - 28 Jan 2024

Cited by 6 | Viewed by 4736

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-β (MENβ) are two long noncoding RNAs upregulated in multiple cancers, marking these RNAs as therapeutic targets. While traditional small-molecule and antisense-based approaches are effective, we report a locked nucleic acid (LNA)-based approach that targets the MALAT1 and MENβ triple helices, structures comprised of a U-rich internal stem-loop and an A-rich tract. Two LNA oligonucleotides resembling the A-rich tract (i.e., A₉GCA₄) were examined: an LNA (L15) and a phosphorothioate LNA (PS-L15). L15 binds tighter than PS-L15 to the MALAT1 and MENβ stem loops, although both L15 and PS-L15 enable RNA•LNA-RNA triple-helix formation. Based on UV thermal denaturation assays, both LNAs selectively stabilize the Hoogsteen interface by 5–13 °C more than the Watson–Crick interface. Furthermore, we show that L15 and PS-L15 displace the A-rich tract from the MALAT1 and MENβ stem loop and methyltransferase-like protein 16 (METTL16) from the METTL16-MALAT1 triple-helix complex. Human colorectal carcinoma (HCT116) cells transfected with LNAs have 2-fold less MALAT1 and MENβ. This LNA-based approach represents a potential therapeutic strategy for the dual targeting of MALAT1 and MENβ. Full article

(This article belongs to the Special Issue Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells)

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16 pages, 9427 KB

Open AccessArticle

Post-Radiotherapy Exosomal Non-Coding RNA and Hemograms for Early Death Prediction in Patients with Cervical Cancer

by Oyeon Cho

Int. J. Mol. Sci. 2024, 25(1), 126; https://doi.org/10.3390/ijms25010126 - 21 Dec 2023

Cited by 6 | Viewed by 1885

Abstract

Concurrent chemo-radiotherapy (CCRT) is linked with accelerated disease progression and early death (ED) in various cancers. This study aimed to assess the association of plasma levels of exosomal non-coding ribonucleic acid (RNA) (ncRNA) and blood cell dynamics with ED prediction in patients with cervical cancer undergoing CCRT. Using propensity score matching, a comparison of complete blood counts (CBCs) was performed among 370 CCRT-treated patients. Differences in ncRNA and messenger RNA (mRNA) expression before and after CCRT in 84 samples from 42 patients (cohort 2) were represented as logarithmic fold change (log₂FC). Networks were constructed to link the CBCs to the RNAs whose expression correlated with ED. From the key RNAs selected using multiple regression of all RNA combinations in the network, CBC dynamics-associated ncRNAs were functionally characterized using an enrichment analysis. Cohort 1 (120 patients) exhibited a correlation between elevated absolute neutrophil counts (ANC) and ED. Cohort 2 exhibited a prevalence of microRNA (miR)-574-3p and long intergenic non-protein coding (LINC)01003 ncRNA, whose expression correlated with ANC and hemoglobin values, respectively. Conversely, acyl-coenzyme A thioesterase 9 (ACOT9) mRNA was relevant to all CBC components. An integrative analysis of post-CCRT ncRNA levels and CBC values revealed that the patients with miR-574-3p-LINC01003-ACOT9 log₂FC) < 0 had a better prospect of 30-month disease-specific survival. These findings indicate that miR-574-3p and LINC01003 could serve as ED prognostic biomarkers. Full article

(This article belongs to the Special Issue Functional Role of Non-coding RNAs in Cancer: Inside and outside Cells)

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