Noncoding RNAs regulate alternative splicing in Cancer

AbstractAS (alternative splicing) is a fundamental process by which a gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in AS influence the occurrence and development of many diseases, including cancers, and are frequently found to participate in various aspects of cancer biology, such as promoting invasion, metastasis, apoptosis resistance and drug resistance. NcRNAs (noncoding RNAs) are an abundant class of RNAs that do not encode proteins. NcRNAs include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular RNAs) and snRNAs (small nuclear RNAs) and have been proven to act as regulatory molecules that mediate cancer processes through AS. NcRNAs can directly or indirectly influence a plethora of molecular targets to regulate cis-acting elements, trans-acting factors, or pre-mRNA transcription at multiple levels, affecting the AS process and generating alternatively spliced isoforms. Consequently, ncRNA-mediated AS outcomes affect multiple cellular signaling pathways that promote or suppress cancer progression. In this review, we summarize the current mechanisms by which ncRNAs regulate AS in cancers and discuss their potential clinical applications as biomarkers and therapeutic targets.

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Circular RNA circFAT1(e2) Promotes Osteosarcoma Progression and Metastasis by Sponging miR-181b and Regulating HK2 Expression

BioMed Research International ◽

10.1155/2020/3589871 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Huijie Gu ◽

Xiangyang Cheng ◽

Jun Xu ◽

Kaifeng Zhou ◽

Chong Bian ◽

...

Keyword(s):

Gene Expression ◽

Cancer Progression ◽

Therapeutic Target ◽

Critical Role ◽

Noncoding Rnas ◽

Circular Rna ◽

Expression Level ◽

Circular Rnas ◽

Competing Endogenous Rna ◽

Potential Therapeutic Target

As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. Nevertheless, how circRNAs participate in osteosarcoma (OS) development and progression are not well understood. In the present study, we identified a circRNA circFAT1(e2) with an upregulated expression level in OS tissues. By functional experiments, we found that circFAT1(e2) depletion significantly suppressed the proliferation and reduced migration in OS. In terms of mechanism, we found that circFAT1(e2) inhibited miR-181b, while miR-181b targeted HK2. By releasing the inhibition of miR-181b on HK2 expression, leading to attenuated OS progression. Mechanistic investigations suggested that circFAT1(e2) served as a competing endogenous RNA (ceRNA) of miR-181b to enhance HK2 expression. On the whole, our study indicated that circFAT1(e2) exerted oncogenic roles in OS and suggested the circFAT1(e2)/miR-181b/HK2 axis might be a potential therapeutic target.

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The Status of p53 Oligomeric and Aggregation States in Cancer

Biomolecules ◽

10.3390/biom10040548 ◽

2020 ◽

Vol 10 (4) ◽

pp. 548 ◽

Cited By ~ 2

Author(s):

Guilherme A. P. de Oliveira ◽

Elaine C. Petronilho ◽

Murilo M. Pedrote ◽

Mayra A. Marques ◽

Tuane C. R. G. Vieira ◽

...

Keyword(s):

Cancer Progression ◽

Cancer Biology ◽

Mutant P53 ◽

Binding Properties ◽

Research Directions ◽

The Status ◽

Multiple Levels ◽

Novel Therapeutic Strategies ◽

The Guardian ◽

Dna Binding Properties

Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases.

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The interplay between microRNA and alternative splicing of linear and circular RNAs in eleven plant species

Bioinformatics ◽

10.1093/bioinformatics/btz038 ◽

2019 ◽

Vol 35 (17) ◽

pp. 3119-3126 ◽

Cited By ~ 5

Author(s):

Huiyuan Wang ◽

Huihui Wang ◽

Hangxiao Zhang ◽

Sheng Liu ◽

Yongsheng Wang ◽

...

Keyword(s):

Alternative Splicing ◽

Plant Species ◽

Single Molecule ◽

Mirna Target ◽

Supplementary Information ◽

Circular Rnas ◽

Sequencing Data ◽

Genomic Locus ◽

Target Sites ◽

Alternatively Spliced

Abstract Motivation MicroRNA (miRNA) and alternative splicing (AS)-mediated post-transcriptional regulation has been extensively studied in most eukaryotes. However, the interplay between AS and miRNAs has not been explored in plants. To our knowledge, the overall profile of miRNA target sites in circular RNAs (circRNA) generated by alternative back splicing has never been reported previously. To address the challenge, we identified miRNA target sites located in alternatively spliced regions of the linear and circular splice isoforms using the up-to-date single-molecule real-time (SMRT) isoform sequencing (Iso-Seq) and Illumina sequencing data in eleven plant species. Results In total, we identified 399 401 and 114 574 AS events from linear and circular RNAs, respectively. Among them, there were 64 781 and 41 146 miRNA target sites located in linear and circular AS region, respectively. In addition, we found 38 913 circRNAs to be overlapping with 45 648 AS events of its own parent isoforms, suggesting circRNA regulation of AS of linear RNAs by forming R-loop with the genomic locus. Here, we present a comprehensive database of miRNA targets in alternatively spliced linear and circRNAs (ASmiR) and a web server for deposition and identification of miRNA target sites located in the alternatively spliced region of linear and circular RNAs. This database is accompanied by an easy-to-use web query interface for meaningful downstream analysis. Plant research community can submit user-defined datasets to the web service to search AS regions harboring small RNA target sites. In conclusion, this study provides an unprecedented resource to understand regulatory relationships between miRNAs and AS in both gymnosperms and angiosperms. Availability and implementation The readily accessible database and web-based tools are available at http://forestry.fafu.edu.cn/bioinfor/db/ASmiR. Supplementary information Supplementary data are available at Bioinformatics online.

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A saga of cancer epigenetics: linking epigenetics to alternative splicing

Biochemical Journal ◽

10.1042/bcj20161047 ◽

2017 ◽

Vol 474 (6) ◽

pp. 885-896 ◽

Cited By ~ 18

Author(s):

Sathiya Pandi Narayanan ◽

Smriti Singh ◽

Sanjeev Shukla

Keyword(s):

Alternative Splicing ◽

Rna Polymerase Ii ◽

Cancer Progression ◽

Rna Binding ◽

Rna Binding Proteins ◽

Epigenetic Modifications ◽

Protein Isoforms ◽

Epigenetic Alterations ◽

Cancer Epigenetics ◽

Alternatively Spliced

The discovery of an increasing number of alternative splicing events in the human genome highlighted that ∼94% of genes generate alternatively spliced transcripts that may produce different protein isoforms with diverse functions. It is now well known that several diseases are a direct and indirect consequence of aberrant splicing events in humans. In addition to the conventional mode of alternative splicing regulation by ‘cis’ RNA-binding sites and ‘trans’ RNA-binding proteins, recent literature provides enormous evidence for epigenetic regulation of alternative splicing. The epigenetic modifications may regulate alternative splicing by either influencing the transcription elongation rate of RNA polymerase II or by recruiting a specific splicing regulator via different chromatin adaptors. The epigenetic alterations and aberrant alternative splicing are known to be associated with various diseases individually, but this review discusses/highlights the latest literature on the role of epigenetic alterations in the regulation of alternative splicing and thereby cancer progression. This review also points out the need for further studies to understand the interplay between epigenetic modifications and aberrant alternative splicing in cancer progression.

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Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy

International Journal of Cell Biology ◽

10.1155/2013/962038 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 62

Author(s):

Serena Bonomi ◽

Stefania Gallo ◽

Morena Catillo ◽

Daniela Pignataro ◽

Giuseppe Biamonti ◽

...

Keyword(s):

Alternative Splicing ◽

Cancer Progression ◽

Cancer Treatments ◽

Splicing Regulators ◽

Transcriptional Regulatory Mechanism ◽

Transcriptional Regulatory ◽

Anti Cancer ◽

Alternatively Spliced ◽

Splicing Isoforms

Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.

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Quantifying full-length circular RNAs in cancer

10.1101/2021.02.04.429722 ◽

2021 ◽

Author(s):

Ken Hung-On Yu ◽

Christina Huan Shi ◽

Bo Wang ◽

Savio Ho-Chit Chow ◽

Grace Tin-Yun Chung ◽

...

Keyword(s):

Experimental Data ◽

Alternative Splicing ◽

Nasopharyngeal Carcinoma ◽

Computational Efficiency ◽

Full Length ◽

Circular Rnas ◽

Sequencing Data ◽

Response Elements ◽

Different Types ◽

Alternatively Spliced

AbstractCircular RNAs (circRNAs) are abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels from RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discover and validate circRNA isoforms differentially expressed between the two groups. Compared to the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain substantially fewer microRNA response elements, demonstrating the importance of quantifying full-length circRNA isoforms.

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CircZFR serves as a prognostic marker to promote bladder cancer progression by regulating miR-377/ZEB2 signaling

Bioscience Reports ◽

10.1042/bsr20192779 ◽

2019 ◽

Vol 39 (12) ◽

Cited By ~ 7

Author(s):

Wen-Yuan Zhang ◽

Qing-Hong Liu ◽

Tie-Jun Wang ◽

Jun Zhao ◽

Xiao-Hua Cheng ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Progression ◽

Cancer Biology ◽

Human Cancer ◽

Migration And Invasion ◽

Circular Rnas ◽

Normal Bladder ◽

Bladder Cancer Cells

Abstract Circular RNAs (circRNAs) have been identified as crucial regulators of gene expression in human cancer biology. CircZFR is a novel identified circRNA and its effect in bladder cancer remains unclearly. In the present study, we aimed to investigate the role of circZFR in the progression of bladder cancer. First, we demonstrated that the expression of circZFR was higher in bladder cancer tissues and cells compared with adjacent non-tumor tissues and normal bladder epithelial cells. And higher circZFR levels were positively correlated with bladder cancer patients’ pathological T stage, grade, lymphatic metastasis, recurrence, progression-free survival (PFS) and overall survival (OS). Functionally, knockdown of circZFR could significantly prohibit cell growth, migration and invasion, arrest cell cycle as well as promote apoptosis of bladder cancer cells in vitro study. Mechanistically, we observed that circZFR could directly bind to miR-377 as sponge to promote ZEB2 expression in bladder cancer cells. In addition, rescue assays demonstrated that restoration of ZEB2 significantly impaired the suppressive effects of circZFR silencing on bladder cancer cells growth, migration and invasion. Taken together, our results illuminated that circZFR could be a prognostic biomarker in bladder cancer and exerted oncogenic roles through regulating miR-377/ZEB2 axis in bladder cancer, which indicated that circZFR could be a potential therapeutic target for bladder cancer patients treatment.

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Quantifying full-length circular RNAs in cancer

Genome Research ◽

10.1101/gr.275348.121 ◽

2021 ◽

pp. gr.275348.121

Author(s):

Ken Hung-On Yu ◽

Christina Huan Shi ◽

Bo Wang ◽

Savio Ho-Chit Chow ◽

Grace Tin-Yun Chung ◽

...

Keyword(s):

Experimental Data ◽

Alternative Splicing ◽

Nasopharyngeal Carcinoma ◽

Computational Efficiency ◽

Full Length ◽

Circular Rnas ◽

Sequencing Data ◽

Response Elements ◽

Different Types ◽

Alternatively Spliced

Circular RNAs (circRNAs) are abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels from RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discover and validate circRNA isoforms differentially expressed between the two groups. Compared to the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain substantially fewer microRNA response elements, demonstrating the importance of quantifying full-length circRNA isoforms.

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Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Cells ◽

10.3390/cells9030760 ◽

2020 ◽

Vol 9 (3) ◽

pp. 760 ◽

Cited By ~ 1

Author(s):

Silvia Belluti ◽

Giovanna Rigillo ◽

Carol Imbriano

Keyword(s):

Transcription Factors ◽

Alternative Splicing ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Splice Variants ◽

Regulatory Elements ◽

Apoptosis Resistance ◽

Clinical Biomarkers ◽

Differentiation Block ◽

Dna Regulatory Elements

Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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Intricate crosstalk between MYB and noncoding RNAs in cancer

Cancer Cell International ◽

10.1186/s12935-021-02362-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dingyu Hu ◽

Wenjun Shao ◽

Li Liu ◽

Yanyan Wang ◽

Shunling Yuan ◽

...

Keyword(s):

Cancer Progression ◽

Rna Processing ◽

Malignant Tumors ◽

Noncoding Rnas ◽

Therapeutic Strategies ◽

Circular Rnas ◽

Biological Functions ◽

Protein Coding ◽

Non Coding Rnas ◽

Myb Proteins

AbstractMYB is often overexpressed in malignant tumors and plays a carcinogenic role in the initiation and development of cancer. Deletion of the MYB regulatory C-terminal domain may be a driving mutation leading to tumorigenesis, therefore, different tumor mechanisms produce similar MYB proteins. As MYB is a transcription factor, priority has been given to identifying the genes that it regulates. All previous attention has been focused on protein-coding genes. However, an increasing number of studies have suggested that MYB can affect the complexity of cancer progression by regulating tumor-associated noncoding RNAs (ncRNAs), such as microRNAs, long-non-coding RNAs and circular RNAs. ncRNAs can regulate the expression of numerous downstream genes at the transcription, RNA processing and translation levels, thereby having various biological functions. Additionally, ncRNAs play important roles in regulating MYB expression. This review focuses on the intricate crosstalk between oncogenic MYB and ncRNAs, which play a pivotal role in tumorigenesis, including proliferation, apoptosis, angiogenesis, metastasis, senescence and drug resistance. In addition, we discuss therapeutic strategies for crosstalk between MYB and ncRNAs to prevent the occurrence and development of cancer.

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