International Journal of Molecular Sciences

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17 pages, 10918 KiB

Open AccessArticle

Single-Cell RNA Sequencing Reveals Extensive Heterogeneity and Unique Gene Trajectories in Non-Transformed and Transformed Human Lung Epithelial Cells: Insights into the Role of LncRNAs in Tumor Heterogeneity

by Sokviseth Moeng, Andres D. Chamorro-Parejo, Minsun S. Jeon, James J. Cai and Kenneth S. Ramos

Int. J. Mol. Sci. 2025, 26(4), 1690; https://doi.org/10.3390/ijms26041690 - 16 Feb 2025

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Abstract

Lung cancer exhibits substantial inter- and intra-tumor heterogeneity, with features that present significant challenges in advancing biomarker discovery and the development of targeted therapeutics. To fill this gap, we employed single-cell RNA sequencing (scRNA-seq) and advanced bioinformatics tools to evaluate the transcriptomic heterogeneity [...] Read more.

Lung cancer exhibits substantial inter- and intra-tumor heterogeneity, with features that present significant challenges in advancing biomarker discovery and the development of targeted therapeutics. To fill this gap, we employed single-cell RNA sequencing (scRNA-seq) and advanced bioinformatics tools to evaluate the transcriptomic heterogeneity of immortalized, non-transformed (BEAS2B) and transformed (H460) lung epithelial cell lines and their responses to carcinogen challenge. Gene expression profiles resolved four primary clusters further discretized into unique subclusters based on genetic signatures and phenotypic profiles. Profiles of long non-coding RNAs (lncRNAs) identified microRNA host genes, antisense RNA genes, divergent transcript, and long intergenic non-coding RNAs as contributors to cellular heterogeneity. These findings indicate that distinct patterns of gene expression, remarkably in lncRNAs, define cellular heterogeneity in non-transformed versus transformed cells. These features can be exploited for the development of therapies directed at specific cell subpopulations in precancerous lesions and within lung tumors. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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18 pages, 4566 KiB

Open AccessArticle

miRNA Signatures in Alveolar Macrophages Related to Cigarette Smoke: Assessment and Bioinformatics Analysis

by Davida Mirra, Renata Esposito, Giuseppe Spaziano, Concetta Rafaniello, Francesca Panico, Antonio Squillante, Maddalena Falciani, Diana Marisol Abrego-Guandique, Eleonora Caiazzo, Luca Gallelli, Erika Cione and Bruno D’Agostino

Int. J. Mol. Sci. 2025, 26(3), 1277; https://doi.org/10.3390/ijms26031277 - 1 Feb 2025

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Abstract

Cigarette smoke (CS) is a driver of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC). Tobacco causes oxidative stress, impaired phagocytosis of alveolar macrophages (AMs), and alterations in gene expression in the lungs of smokers. MicroRNAs [...] Read more.

Cigarette smoke (CS) is a driver of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC). Tobacco causes oxidative stress, impaired phagocytosis of alveolar macrophages (AMs), and alterations in gene expression in the lungs of smokers. MicroRNAs (miRNAs) are small non-coding RNAs that influence several regulatory pathways. Previously, we monitored the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p, and 106a-5p in AMs derived from the bronchoalveolar lavage (BAL) of subjects with NSCLC, COPD, and smoker and non-smoker control groups. Here, we investigated the capability of CS conditionate media to modulate the abovementioned miRNAs in primary AMs obtained in the same 43 sex-matched subjects. The expressions of has-miR-34a-5p, 17-5p, 16-5p, 106a-5p, 223-5p, and 20a-5p were assessed before and after in vitro CS exposure by RT-PCR. In addition, a comprehensive bioinformatic analysis of miRNAs KEGGS and PPI linked to inflammation was performed. Distinct and common miRNA expression profiles were identified in response to CS, suggesting their possible role in smoking-related diseases. It is worth noting that, following exposure to CS, the expression levels of hsa-miR-34a-5p and 17-5p in both smokers and non-smokers, 106a-5p in non-smokers, and 20a-5p in smokers, shifted towards those found in individuals with COPD, suggesting them as a risk factor in developing this lung condition. Moreover, CS-focused sub-analysis identified miRNA which exhibited CS-dependent pattern and modulated mRNA involved in the immune system or AMs property regulation. In conclusion, our study uncovered miRNA signatures in AMs exposed to CS, indicating that CS might modify epigenetic patterns that contribute to macrophage activation and lung disease onset and progression. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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16 pages, 7913 KiB

Open AccessArticle

Identification and Evaluation of Hub Long Non-Coding RNAs and mRNAs in PM2.5-Induced Lung Cell Injury

by Jing Sui, Yanni Zhang, Linjie Zhang and Hui Xia

Int. J. Mol. Sci. 2025, 26(3), 911; https://doi.org/10.3390/ijms26030911 - 22 Jan 2025

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Abstract

Exposure to air pollution, especially fine particulate matter (PM2.5), is closely linked to various adverse health effects, particularly in the respiratory system. The present study was designed to investigate the lncRNA–mRNA interactions in PM2.5-induced lung cell injury using weighted gene co-expression network analysis [...] Read more.

Exposure to air pollution, especially fine particulate matter (PM2.5), is closely linked to various adverse health effects, particularly in the respiratory system. The present study was designed to investigate the lncRNA–mRNA interactions in PM2.5-induced lung cell injury using weighted gene co-expression network analysis (WGCNA). We downloaded the gene expression data of GSE138870 from the Gene Expression Omnibus (GEO) database and screened for differentially expressed lncRNAs and mRNAs. We constructed co-expression modules with WGCNA. Furthermore, functional enrichment analysis was also performed. We also constructed lncRNA–mRNA co-expression networks and lncRNA–mRNA-pathway networks to identify key regulatory relationships. The results revealed several modules significantly correlated with PM2.5-induced lung injury, such as the turquoise and blue modules. Genes within these modules were enriched in pathways related to signal transduction, metabolism, and cancer. Hub lncRNAs in the turquoise module, including LOC100129034 and CROCCP2, were found to be co-expressed with mRNAs involved in apoptosis and proliferation regulation. In the blue module, lnc-CLVS2-2 and GARS1-DT were connected to genes related to cell migration, invasion, and lung injury. These findings contribute novel perspectives to the molecular mechanisms involved in PM2.5-induced lung injury and suggest that WGCNA could be a valuable tool for predicting and understanding this disease process. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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11 pages, 1825 KiB

Open AccessArticle

The Expression of miR-211-5p in Sentinel Lymph Node Metastases of Malignant Melanoma Is a Potential Marker for Poor Prognosis

by Rose Kathrin Caroline Moritz, Nicole Ebelt, Tina Rattay, Jovine Ehrenreich, Cord Sunderkötter and Dennis Gerloff

Int. J. Mol. Sci. 2024, 25(19), 10859; https://doi.org/10.3390/ijms251910859 - 9 Oct 2024

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Abstract

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and [...] Read more.

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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22 pages, 4365 KiB

Open AccessArticle

Extracellular RNAs from Whole Urine to Distinguish Prostate Cancer from Benign Prostatic Hyperplasia

by Michele Stella, Giorgio Ivan Russo, Rosario Leonardi, Daniela Carcò, Giuseppe Gattuso, Luca Falzone, Carmen Ferrara, Angela Caponnetto, Rosalia Battaglia, Massimo Libra, Davide Barbagallo, Cinzia Di Pietro, Salvatore Pernagallo, Cristina Barbagallo and Marco Ragusa

Int. J. Mol. Sci. 2024, 25(18), 10079; https://doi.org/10.3390/ijms251810079 - 19 Sep 2024

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Abstract

RNAs, especially non-coding RNAs (ncRNAs), are crucial players in regulating cellular mechanisms due to their ability to interact with and regulate other molecules. Altered expression patterns of ncRNAs have been observed in prostate cancer (PCa), contributing to the disease’s initiation, progression, and treatment [...] Read more.

RNAs, especially non-coding RNAs (ncRNAs), are crucial players in regulating cellular mechanisms due to their ability to interact with and regulate other molecules. Altered expression patterns of ncRNAs have been observed in prostate cancer (PCa), contributing to the disease’s initiation, progression, and treatment response. This study aimed to evaluate the ability of a specific set of RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and mRNAs, to discriminate between PCa and the non-neoplastic condition benign prostatic hyperplasia (BPH). After selecting by literature mining the most relevant RNAs differentially expressed in biofluids from PCa patients, we evaluated their discriminatory power in samples of unfiltered urine from 50 PCa and 50 BPH patients using both real-time PCR and droplet digital PCR (ddPCR). Additionally, we also optimized a protocol for urine sample manipulation and RNA extraction. This two-way validation study allowed us to establish that miRNAs (i.e., miR-27b-3p, miR-574-3p, miR-30a-5p, and miR-125b-5p) are more efficient biomarkers for PCa compared to long RNAs (mRNAs and lncRNAs) (e.g., PCA3, PCAT18, and KLK3), as their dysregulation was consistently reported in the whole urine of patients with PCa compared to those with BPH in a statistically significant manner regardless of the quantification methodology performed. Moreover, a significant increase in diagnostic performance was observed when molecular signatures composed of different miRNAs were considered. Hence, the abovementioned circulating ncRNAs represent excellent potential non-invasive biomarkers in urine capable of effectively distinguishing individuals with PCa from those with BPH, potentially reducing cancer overdiagnosis. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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Review

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17 pages, 2794 KiB

Open AccessReview

Long Non-Coding TP73-AS1: A Potential Biomarker and Therapeutic Target in Cancer

by Kejing Li, Dapeng Zhao, Xuena Liu, Qiyou Cao, Longzhu Ruan, Huiwen Lei, Xiaohua Chen, Xiaodong Jin, Qiang Li, Xiaodong Xie and Cuixia Di

Int. J. Mol. Sci. 2025, 26(8), 3886; https://doi.org/10.3390/ijms26083886 - 20 Apr 2025

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Abstract

Tumor protein 73 antisense RNA 1 (TP73-AS1), a newly discovered long non-coding RNA (lncRNA), the dysregulated expression of which is closely related to the occurrence, drug resistance, and prognosis of various cancers. Exploring the regulatory mechanism of TP73-AS1 provides a new research direction [...] Read more.

Tumor protein 73 antisense RNA 1 (TP73-AS1), a newly discovered long non-coding RNA (lncRNA), the dysregulated expression of which is closely related to the occurrence, drug resistance, and prognosis of various cancers. Exploring the regulatory mechanism of TP73-AS1 provides a new research direction for cancer diagnosis and treatment. On this basis, we briefly review the molecular structural and dual regulatory roles of TP73-AS1 in cancer. In addition, we outline its three molecular mechanisms in cancer: binding to proteins, regulating signaling pathways, and serving as molecular sponges. Subsequently, we introduce the role of TP73-AS1 in common malignant tumors such as gastric cancer (GC), lung cancer, colorectal cancer (CRC), etc. Last, emphasis is given to the potential clinical value of TP73-AS1, especially as single nucleotide polymorphisms of this lncRNA are associated with the risk of GC and CRC. Therefore, this review highlights the significance of TP73-AS1 as a novel biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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19 pages, 1147 KiB

Open AccessReview

The Application of Non-Coding RNAs as Biomarkers, Therapies, and Novel Vaccines in Diseases

by Lu-Xuan Yang, Hui Li, Zhi-Hui Cheng, He-Yue Sun, Jie-Ping Huang, Zhi-Peng Li, Xin-Xin Li, Zhi-Gang Hu and Jian Wang

Int. J. Mol. Sci. 2025, 26(7), 3055; https://doi.org/10.3390/ijms26073055 - 26 Mar 2025

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Abstract

Non-coding RNAs (ncRNAs) are a class of RNAs that largely lack the capacity to encode proteins. They have garnered significant attention due to their central regulatory functions across numerous cellular and physiological processes at transcriptional, post-transcriptional, and translational levels. Over the past decade, [...] Read more.

Non-coding RNAs (ncRNAs) are a class of RNAs that largely lack the capacity to encode proteins. They have garnered significant attention due to their central regulatory functions across numerous cellular and physiological processes at transcriptional, post-transcriptional, and translational levels. Over the past decade, ncRNA-based therapies have gained considerable attention in the diagnosis, treatment, and prevention of diseases, and many studies have revealed a significant relationship between ncRNAs and diseases. At the same time, due to their tissue specificity, an increasing number of projects have focused on the application of ncRNAs as biomarkers in diseases, as well as the design and development of novel ncRNA-based vaccines and therapies for clinical use. These ncRNAs may also drive research into the potential molecular mechanisms and complex pathogenesis of related diseases. However, new biomarkers need to be validated for their clinical effectiveness. Additionally, to produce safe and stable RNA products, factors such as purity, precise dosage, and effective delivery methods must be ensured to achieve optimal bioactivity. These challenges remain key issues in the clinical application of ncRNAs. This review summarizes the prospects of ncRNAs as potential biomarkers, as well as the current research status and clinical applications of ncRNAs in therapies and vaccines, and discusses the challenges and expectations of ncRNAs in disease diagnosis and drug therapy. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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20 pages, 958 KiB

Open AccessReview

mirSNPs as Potential Colorectal Cancer Biomarkers: A Systematic Review

by Katiusse Alves dos Santos, Lourdes Maria Costa Alves de Sousa, Karla Simone Costa de Souza, Olalla Maroñas Amigo, André Ducati Luchessi and Vivian Nogueira Silbiger

Int. J. Mol. Sci. 2024, 25(23), 12975; https://doi.org/10.3390/ijms252312975 - 3 Dec 2024

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Abstract

Colorectal cancer (CRC) is the third most common neoplasm in the world and the second with the highest mortality rate. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes known as mirSNPs may be related to dysregulated miRNA expression in several neoplasms. This systematic [...] Read more.

Colorectal cancer (CRC) is the third most common neoplasm in the world and the second with the highest mortality rate. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes known as mirSNPs may be related to dysregulated miRNA expression in several neoplasms. This systematic review aims to investigate studies that investigate SNPs located in regions of miRNA genes that influence their expression and are associated with CRC, as well as their potential as biomarkers for the disease, based on the available literature. For this, searches were performed in public databases, including MEDLINE/PubMed, Embase, Web of Science, and Scopus. The rigorous review of the PRISMA 2020 guidelines and the methodological quality of these studies was assessed using the Newcastle–Ottawa scale and the Mixed Methods Assessment Tool. Of the 175 studies identified, 26 were considered eligible: 18 of them highlighted mirSNPs as potential biomarkers of risk and prognosis for CRC; 4 studies suggested a protective role; 1 study linked mirSNPs to treatment; 3 studies found no relevant evidence. These results highlight the importance of conducting further research on the topic, given the potential of these biomarkers to contribute to risk assessment, prognosis, and the development of therapeutic strategies for patients with CRC. Full article

(This article belongs to the Special Issue Roles and Mechanisms of Non-Coding RNAs in Human Health and Disease)

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