International Journal of Molecular Sciences

Editorial

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2 pages, 185 KiB

Open AccessEditorial

The Emerging Role of RNA in Diseases and Cancers

by Alessandro Fatica

Int. J. Mol. Sci. 2023, 24(7), 6682; https://doi.org/10.3390/ijms24076682 - 03 Apr 2023

Viewed by 908

Abstract

In recent years, there has been a growing interest in the role of RNA in diseases and cancers [...] Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

Research

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15 pages, 3338 KiB

Open AccessArticle

LINC01605 Is a Novel Target of Mutant p53 in Breast and Ovarian Cancer Cell Lines

by Michela Coan, Martina Toso, Laura Cesaratto, Ilenia Rigo, Silvia Borgna, Anna Dalla Pietà, Luigi Zandonà, Lorenzo Iuri, Antonella Zucchetto, Carla Piazza, Gustavo Baldassarre, Riccardo Spizzo and Milena Sabrina Nicoloso

Int. J. Mol. Sci. 2023, 24(18), 13736; https://doi.org/10.3390/ijms241813736 - 06 Sep 2023

Viewed by 945

Abstract

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the [...] Read more.

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the transcription of both protein-coding and non-protein-coding genes. Gain-of-function of mut_p53 triggers modification in gene expression as well; however, the impact of mut_p53 on the transcription of the non-protein-coding genes and whether these non-protein-coding genes affect oncogenic properties of cancer cell lines are not fully explored. In this study, we suggested that LINC01605 (also known as lincDUSP) is a long non-coding RNA regulated by mut_p53 and proved that mut_p53 directly regulates LINC01605 by binding to an enhancer region downstream of the LINC01605 locus. We also showed that the loss or downregulation of LINC01605 impairs cell migration in a breast cancer cell line. Eventually, by performing a combined analysis of RNA-seq data generated in mut_TP53-silenced and LINC01605 knockout cells, we showed that LINC01605 and mut_p53 share common gene pathways. Overall, our findings underline the importance of ncRNAs in the mut_p53 network in breast and ovarian cancer cell lines and in particular the importance of LINC01605 in mut_p53 pro-migratory pathways. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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24 pages, 4342 KiB

Open AccessArticle

FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation

by Alessio Colantoni, Davide Capauto, Vincenzo Alfano, Eleonora D’Ambra, Sara D’Uva, Gian Gaetano Tartaglia and Mariangela Morlando

Int. J. Mol. Sci. 2023, 24(4), 3181; https://doi.org/10.3390/ijms24043181 - 06 Feb 2023

Cited by 5 | Viewed by 2537

Abstract

Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for [...] Read more.

Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutations of the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays a pivotal role in splicing regulation and its mutations severely alter the exon composition of transcripts coding for proteins involved in neurogenesis, axon guidance, and synaptic activity. In this study, by using in vitro-derived human MNs, we investigate the effect of the P525L FUS mutation on non-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observed altered levels of circRNAs in FUS^P525L MNs and a preferential binding of the mutant protein to introns flanking downregulated circRNAs and containing inverted Alu repeats. For a subset of circRNAs, FUS^P525L also impacts their nuclear/cytoplasmic partitioning, confirming its involvement in different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAs to act as miRNA sponges, with possible implications in ALS pathogenesis. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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Review

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17 pages, 767 KiB

Open AccessReview

Mechanisms of Long Non-Coding RNA in Breast Cancer

by Bianca Giuliani, Chiara Tordonato and Francesco Nicassio

Int. J. Mol. Sci. 2023, 24(5), 4538; https://doi.org/10.3390/ijms24054538 - 25 Feb 2023

Cited by 8 | Viewed by 2383

Abstract

The landscape of pervasive transcription in eukaryotic genomes has made space for the identification of thousands of transcripts that are difficult to frame in a specific functional category. A new class has been broadly named as long non-coding RNAs (lncRNAs) and shortly defined [...] Read more.

The landscape of pervasive transcription in eukaryotic genomes has made space for the identification of thousands of transcripts that are difficult to frame in a specific functional category. A new class has been broadly named as long non-coding RNAs (lncRNAs) and shortly defined as transcripts that are longer than 200 nucleotides with no or limited coding potential. So far, about 19,000 lncRNAs genes have been annotated in the human genome (Gencode 41), nearly matching the number of protein-coding genes. A key scientific priority is the functional characterization of lncRNAs, a major challenge in molecular biology that has encouraged many high-throughput efforts. LncRNA studies have been stimulated by the enormous clinical potential that these molecules promise and have been based on the characterization of their expression and functional mechanisms. In this review, we illustrate some of these mechanisms as they have been pictured in the context of breast cancer. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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13 pages, 944 KiB

Open AccessReview

Regulation of Gene Expression by m6Am RNA Modification

by Bianca Cesaro, Marco Tarullo and Alessandro Fatica

Int. J. Mol. Sci. 2023, 24(3), 2277; https://doi.org/10.3390/ijms24032277 - 23 Jan 2023

Cited by 11 | Viewed by 2861

Abstract

The field of RNA modification, also referred to as “epitranscriptomics,” is gaining more and more interest from the scientific community. More than 160 chemical modifications have been identified in RNA molecules, but the functional significance of most of them still needs to be [...] Read more.

The field of RNA modification, also referred to as “epitranscriptomics,” is gaining more and more interest from the scientific community. More than 160 chemical modifications have been identified in RNA molecules, but the functional significance of most of them still needs to be clarified. In this review, we discuss the role of N⁶,2′-O-dimethyladenosine (m⁶A_m) in gene expression regulation. m⁶A_m is present in the first transcribed nucleotide close to the cap in many mRNAs and snRNAs in mammals and as internal modification in the snRNA U2. The writer and eraser proteins for these modifications have been recently identified and their deletions have been utilized to understand their contributions in gene expression regulation. While the role of U2 snRNA-m⁶A_m in splicing regulation has been reported by different independent studies, conflicting data were found for the role of cap-associated m⁶A_m in mRNA stability and translation. However, despite the open debate on the role of m⁶A_m in mRNA expression, the modulation of regulators produced promising results in cancer cells. We believe that the investigation on m⁶A_m will continue to yield relevant results in the future. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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17 pages, 661 KiB

Open AccessReview

Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer

by Silvia Anna Ciafrè, Monia Russo, Alessandro Michienzi and Silvia Galardi

Int. J. Mol. Sci. 2023, 24(3), 1828; https://doi.org/10.3390/ijms24031828 - 17 Jan 2023

Cited by 4 | Viewed by 1904

Abstract

Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on [...] Read more.

Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on a larger scale, are deemed responsible not only for tumor initiation but also for recurrent tumors, often resistant to chemotherapy and radiotherapy. Long noncoding RNAs are RNA molecules longer than 200 nt, lacking the ability to code for proteins, with recognized roles as fine regulators of gene expression. They can exert these functions through a variety of mechanisms, acting at almost all steps of gene expression, from modulation of the epigenetic state of chromatin to modulation of protein stability. In all cases, lncRNAs do not work alone, but they always interact with other RNA molecules, either coding or non-coding, or with protein factors. In this review, we summarize the latest results obtained about the involvement of lncRNAs in the initiating cells of several types of tumors, and highlight the different mechanisms through which they work, while discussing how the modulation of a lncRNA can affect several aspects of tumor onset and progression. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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13 pages, 1128 KiB

Open AccessReview

Emerging Roles for the RNA-Binding Protein HuD (ELAVL4) in Nervous System Diseases

by Beatrice Silvestri, Michela Mochi, Maria Giovanna Garone and Alessandro Rosa

Int. J. Mol. Sci. 2022, 23(23), 14606; https://doi.org/10.3390/ijms232314606 - 23 Nov 2022

Cited by 7 | Viewed by 1792

Abstract

The main goal of this review is to provide an updated overview of the involvement of the RNA-binding protein (RBP) HuD, encoded by the ELAVL4 gene, in nervous system development, maintenance, and function, and its emerging role in nervous system diseases. A particular [...] Read more.

The main goal of this review is to provide an updated overview of the involvement of the RNA-binding protein (RBP) HuD, encoded by the ELAVL4 gene, in nervous system development, maintenance, and function, and its emerging role in nervous system diseases. A particular focus is on recent studies reporting altered HuD levels, or activity, in disease models and patients. Substantial evidence suggests HuD involvement in Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). Interestingly, while possible disease-causing mutations in the ELAVL4 gene remain elusive, a common theme in these diseases seems to be the altered regulation of HuD at multiple steps, including post-transcriptional and post-translational levels. In turn, the changed activity of HuD can have profound implications for its target transcripts, which are overly stabilized in case of HuD gain of function (as proposed in PD and ALS) or reduced in case of decreased HuD binding (as suggested by some studies in AD). Moreover, the recent discovery that HuD is a component of pathological cytoplasmic inclusion in both familial and sporadic ALS patients might help uncover the common molecular mechanisms underlying such complex diseases. We believe that deepening our understanding of the involvement of HuD in neurodegeneration could help developing new diagnostic and therapeutic tools. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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12 pages, 3315 KiB

Open AccessReview

Multiple Roles of m6A RNA Modification in Translational Regulation in Cancer

by Guillermo Fernandez Rodriguez, Bianca Cesaro and Alessandro Fatica

Int. J. Mol. Sci. 2022, 23(16), 8971; https://doi.org/10.3390/ijms23168971 - 11 Aug 2022

Cited by 11 | Viewed by 2375

Abstract

Despite its discovery in the early 1970s, m⁶A modification within mRNA molecules has only powerfully entered the oncology field in recent years. This chemical modification can control all aspects of the maturation of mRNAs, both in the nucleus and in the [...] Read more.

Despite its discovery in the early 1970s, m⁶A modification within mRNA molecules has only powerfully entered the oncology field in recent years. This chemical modification can control all aspects of the maturation of mRNAs, both in the nucleus and in the cytoplasm. Thus, the alteration in expression levels of writers, erasers, and readers may significantly contribute to the alteration of gene expression observed in cancer. In particular, the activation of oncogenic pathways can lead to an alteration of the global rate of mRNA translation or the selective translation of specific mRNAs. In both cases, m⁶A can play an important role. In this review, we highlight the role of m⁶A in the regulation of translation by focusing on regulatory mechanisms and cancer-related functions of this novel but still controversial field. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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13 pages, 946 KiB

Open AccessReview

MicroRNAs in Dystrophinopathy

by Ahyoung Lee, Jiwon Moon, Jin Yu and Changwon Kho

Int. J. Mol. Sci. 2022, 23(14), 7785; https://doi.org/10.3390/ijms23147785 - 14 Jul 2022

Cited by 4 | Viewed by 2077

Abstract

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which represent the range of dystrophinopathies, account for nearly 80% of muscle dystrophy. DMD and BMD result from the loss of a functional dystrophin protein, and the leading cause of death in these patients [...] Read more.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which represent the range of dystrophinopathies, account for nearly 80% of muscle dystrophy. DMD and BMD result from the loss of a functional dystrophin protein, and the leading cause of death in these patients is cardiac remodeling and heart failure. The pathogenesis and progression of the more severe form of DMD have been extensively studied and are controlled by many determinants, including microRNAs (miRNAs). The regulatory role of miRNAs in muscle function and the differential miRNA expression in muscular dystrophy indicate the clinical significance of miRNAs. This review discusses the relevant microRNAs as potential biomarkers and therapeutic targets for DMD and DMD cardiomyopathy as examples of dystrophinopathies. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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17 pages, 1397 KiB

Open AccessReview

Next RNA Therapeutics: The Mine of Non-Coding

by Sabrina Garbo, Rossella Maione, Marco Tripodi and Cecilia Battistelli

Int. J. Mol. Sci. 2022, 23(13), 7471; https://doi.org/10.3390/ijms23137471 - 05 Jul 2022

Cited by 34 | Viewed by 3031

Abstract

The growing knowledge on several classes of non-coding RNAs (ncRNAs) and their different functional roles has aroused great interest in the scientific community. Beyond the Central Dogma of Biology, it is clearly known that not all RNAs code for protein products, and they [...] Read more.

The growing knowledge on several classes of non-coding RNAs (ncRNAs) and their different functional roles has aroused great interest in the scientific community. Beyond the Central Dogma of Biology, it is clearly known that not all RNAs code for protein products, and they exert a broader repertoire of biological functions. As described in this review, ncRNAs participate in gene expression regulation both at transcriptional and post-transcriptional levels and represent critical elements driving and controlling pathophysiological processes in multicellular organisms. For this reason, in recent years, a great boost was given to ncRNA-based strategies with potential therapeutic abilities, and nowadays, the use of RNA molecules is experimentally validated and actually exploited in clinics to counteract several diseases. In this review, we summarize the principal classes of therapeutic ncRNA molecules that are potentially implied in disease onset and progression, which are already used in clinics or under clinical trials, highlighting the advantages and the need for a targeted therapeutic strategy design. Furthermore, we discuss the benefits and the limits of RNA therapeutics and the ongoing development of delivery strategies to limit the off-target effects and to increase the translational application. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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Other

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13 pages, 2970 KiB

Open AccessCase Report

Primary Breast Angiosarcoma: Comparative Transcriptome Analysis

by Andrés Rincón-Riveros, Jairo De la Peña, Wilson Rubiano, Fabio Olivella, María Martinez-Agüero and Victoria E. Villegas

Int. J. Mol. Sci. 2022, 23(24), 16032; https://doi.org/10.3390/ijms232416032 - 16 Dec 2022

Cited by 1 | Viewed by 1664

Abstract

Primary breast angiosarcoma, with de novo appearance and not associated with exposure to radiation or lymphedema, is a rare pathology representing less than 0.05% of the neoplasms related to this organ. The pathology is characterized by its aggressiveness, poor prognosis, and difficulties in [...] Read more.

Primary breast angiosarcoma, with de novo appearance and not associated with exposure to radiation or lymphedema, is a rare pathology representing less than 0.05% of the neoplasms related to this organ. The pathology is characterized by its aggressiveness, poor prognosis, and difficulties in its differential diagnosis. This article reports the case of a 55-year-old white woman with no family history of cancer, with a rapidly growing mass in the left mammary gland that ulcerates and bleeds. It is confirmed as primary breast angiosarcoma by immunostaining in the tumor tissue for CD31, CD34, and FLI-1. In addition, a sample of neoplastic and healthy tissues is collected from the patient for RNA sequencing; the results are contrasted with a tissue sample from a patient with Luminal A subtype of breast cancer, as well as data from other cases of angiosarcoma available in public databases. These findings revealed a genetic profile associated with the immune and inflammatory response in the patient’s sample when compared to available angiosarcoma data; these molecular patterns are consistent with other recent studies. Due to the rarity of the disease, the studies carried out on each patient contribute to the expanding knowledge of the etiology and molecular pathways that are still partially known and continue to be the subject of research. Aside from a comparative transcriptome study, this article aims to provide an update on the state of knowledge about this disease. Full article

(This article belongs to the Special Issue The Emerging Role of RNA in Diseases and Cancers)

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