scholarly journals Aberrant RNA Splicing in Cancer and Drug Resistance

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 458 ◽  
Author(s):  
Bi-Dar Wang ◽  
Norman Lee
Keyword(s):  
Drug Resistance ◽  
Rna Splicing ◽  
Splice Variants ◽  
Therapy Resistance ◽  
Protein Isoforms ◽  
Braf V600e ◽  
Aberrant Splice ◽  
Aberrant Splicing ◽  
Aberrant Rna ◽  
Oncogenic Protein

More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-γ, IK6, p61 BRAF V600E, CD19-∆2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms.

scholarly journals In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 680 ◽  
Author(s):  
Asmaa Samy ◽  
Baris Suzek ◽  
Mehmet Ozdemir ◽  
Ozge Sensoy
Keyword(s):  
Rna Splicing ◽  
In Silico Analysis ◽  
Therapy Resistance ◽  
Mrna Splicing ◽  
Splicing Factor ◽  
Cancer Types ◽  
Dynamics Simulations ◽  
Aberrant Rna ◽  
The Impact ◽  
Splicing Machinery

Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations. In this work, the impact of the splicing factor 3B subunit 1 (SF3B1) K700E mutation, a highly prevalent mutation in various cancer types, is investigated through molecular dynamics simulations. Based on our results, K700E mutation increases flexibility of the mutant SF3B1. Consequently, this mutation leads to i) disruption of interaction of pre-mRNA with SF3B1 and p14, thus preventing proper alignment of mRNA and causing usage of abnormal 3’ splice site, and ii) disruption of communication in critical regions participating in interactions with other proteins in pre-mRNA splicing machinery. We anticipate that this study enhances our understanding of the mechanism of functional abnormalities associated with splicing machinery, thereby, increasing possibility for designing effective therapies to combat cancer at an earlier stage.

scholarly journals Aberrant splicing in maize rough endosperm3 reveals a conserved role for U12 splicing in eukaryotic multicellular development

2017 ◽  
Vol 114 (11) ◽  
pp. E2195-E2204 ◽  
Author(s):  
Christine M. Gault ◽  
Federico Martin ◽  
Wenbin Mei ◽  
Fang Bai ◽  
Joseph B. Black ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Splicing ◽  
Protein Glycosylation ◽  
Protein Isoforms ◽  
Aberrant Splicing ◽  
Interacting Protein ◽  
Multicellular Development ◽  
Splicing Efficiency ◽  
Splicing Defects ◽  
Differentiation And Proliferation

RNA splicing of U12-type introns functions in human cell differentiation, but it is not known whether this class of introns has a similar role in plants. The maize ROUGH ENDOSPERM3 (RGH3) protein is orthologous to the human splicing factor, ZRSR2. ZRSR2 mutations are associated with myelodysplastic syndrome (MDS) and cause U12 splicing defects. Maize rgh3 mutants have aberrant endosperm cell differentiation and proliferation. We found that most U12-type introns are retained or misspliced in rgh3. Genes affected in rgh3 and ZRSR2 mutants identify cell cycle and protein glycosylation as common pathways disrupted. Transcripts with retained U12-type introns can be found in polysomes, suggesting that splicing efficiency can alter protein isoforms. The rgh3 mutant protein disrupts colocalization with a known ZRSR2-interacting protein, U2AF2. These results indicate conserved function for RGH3/ZRSR2 in U12 splicing and a deeply conserved role for the minor spliceosome to promote cell differentiation from stem cells to terminal fates.

scholarly journals Alternative Splicing of a Novel Glycophorin Allele GPHe(GL) Generates Two Protein Isoforms in the Human Erythrocyte Membrane

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 391-397
Author(s):  
Cheng-Han Huang ◽  
Olga O. Blumenfeld ◽  
Marion E. Reid ◽  
Ying Chen ◽  
Geoff L. Daniels ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Splice Site ◽  
Rna Splicing ◽  
Phenotypic Diversity ◽  
Full Length ◽  
Protein Isoforms ◽  
Membrane Domain ◽  
Acceptor Splice Site ◽  
Variable Expression ◽  
Aberrant Rna

The Henshaw antigen (synonym: He or MNS6) is carried by an altered form of glycophorin B (GPB), but the molecular basis for its variable expression or quantitative polymorphism remains largely undefined. We report here the identification and analysis of a novel glycophorin He allele, GPHe(GL), which gives rise to the expression of two protein isoforms in the erythrocyte membrane. In addition to the nucleotide changes defining the epitopic sequence of He, a single C-to-G nucleotide transversion in exon V coding for the membrane domain was found to cause aberrant RNA splicings by creating a new acceptor splice site. In addition, a T-to-G transversion at −6 position of the acceptor splice site for exon IV was identified. Both full-length and truncated transcripts of GPHe(GL) were detected as the result of partial activation of the new acceptor splice site and partial inactivation of the normal splice sites. The full-length cDNA encoded He, S, and U antigens, whereas the three truncated ones lacked either the sequence for S and U antigens or a large portion of the membrane domain or both. The GPB gene on the other chromosome was apparently normal and its transcript encoded N, s, and U antigens. These results correlate alternative RNA splicing with the expression of two GPHe isoforms and thus delineate a new mechanism for the phenotypic diversity of membrane glycophorins.

Polymorphisms in the Hyaluronan Synthase 1 Gene May Be Predisposing Factors for Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1363-1363 ◽  
Author(s):  
Sophia Adamia ◽  
Steven P. Treon ◽  
Michael J. Mant ◽  
Loree M. Larratt ◽  
Tony Reiman ◽  
...  
Keyword(s):  
Expression Analysis ◽  
Splice Variants ◽  
Exon Skipping ◽  
Full Length ◽  
Hyaluronan Synthase ◽  
Aberrant Splice ◽  
Splice Sites ◽  
Aberrant Splicing ◽  
Healthy Donors ◽  
Donor And Acceptor

Abstract The hyaluronan synthase 1 gene (HAS1), which maps to chromosome location 19q13.4 encodes a plasma membrane protein, which synthesizes hyaluronan (HA), an extracellular matrix molecule. Previously, in WM patients we detected up-regulation of HAS1 transcripts and identified aberrant splice variants of this gene, termed HAS1Va, Vb, and Vc. In patients with multiple myeloma, expression of HAS1Vb either alone or in combination with HAS1 and other variants strongly correlates with poor survival (P=0.001). Our gene expression analysis of the HAS1 family members demonstrated that 76–97% of individual CD20+ IgM+ WM cells obtained from BM aspirates and from blood (PBMC) express HAS1Va or HAS1Vb aberrant splice variants, often in the absence of full length HAS1 transcripts. Aberrant splicing of HAS1 is the result of activation of cryptic splice sites, which lead to exon skipping and/or intron retention. In turn, activation of cryptic donor and acceptor splice sites of the gene can be promoted by the mutations occurring upstream of these sites and/or at the branch point of slicing. We measured the frequency of a known polymorphism in the HAS1 gene of 16 BM and 30 PB samples obtained from WM patients, in comparison with PBMC samples from 33 healthy donors. Our results indicate that in healthy individuals, the frequency of the two alleles each reached 50% perhaps reflecting stabilizing selection. The majority of healthy donors (61%) are heterozygous for the HAS1 gene polymorphism. In contrast, 92% of analyzed WM patients are homozygous for this same polymorphism. An expression analysis of HAS1 and variants in BM cells and PBMC obtained from the same group of WM patients demonstrated that only those patients who were homozygous for the HAS1 polymorphism express HAS1 and/or its variants. The few WM patients who are heterozygous for this polymorphism have no detectable expression of aberrantly spliced HAS1 variants or full length of HAS1, a phenotype identical to that of healthy donors. Thus, our observations so far suggest that polymorphisms in HAS1 may contribute to aberrations such as exon skipping and/or activation of a new cryptic splice site leading to aberrant splicing of HAS. Based on the results obtained thus far, we speculate that individuals who are homozygous for HAS1 polymorphism(s) are at enhanced risk of developing WM due to a predisposition towards aberrant HAS1 splicing and expression of HAS1 variants, with predicted oncogenic consequences. However, the study of a much larger number of patients and healthy donors is needed to confirm these speculations and to evaluate the prognostic significance of these findings.

Characterization of the aberrant splicing of MAP3K7 induced by cancer-associated SF3B1 mutation

2021 ◽  
Author(s):  
Zhuang Li ◽  
Bo Zhao ◽  
Yueru Shi ◽  
Yuqi Liang ◽  
Rui Qian ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Premature Termination Codon ◽  
Splice Sites ◽  
Polypyrimidine Tract ◽  
Aberrant Splicing ◽  
Nonsense Mediated Decay ◽  
Aberrant Rna ◽  
Branchpoint Sequence

Abstract SF3B1, an essential RNA splicing factor, is frequently mutated in various types of cancers, and the cancer-associated SF3B1 mutation causes aberrant RNA splicing. The aberrant splicing of several transcripts, including MAP3K7, promotes tumorigenesis. Here, we identify a premature termination codon in the aberrantly spliced transcript of MAP3K7. Treatment of HEK293T cells transfected with the K700E-mutated SF3B1 with cycloheximide leads to increased accumulation of the aberrant spliced transcript of MAP3K7, demonstrating that the aberrantly spliced transcript of MAP3K7 is targeted by nonsense-mediated decay. The aberrantly spliced MAP3K7 transcript uses an aberrant 3’ splice sites and an alternative branchpoint sequence. In addition, the aberrant splicing of MAP3K7 requires not only the polypyrimidine tract associated with normal splicing but also an alternative polypyrimidine tract upstream of the aberrant 3’ splice site. Other cancer-associated SF3B1 mutations also cause the aberrant splicing of MAP3K7, which depends on the same sequence features. Our data provide a further understanding of the mechanisms underlying aberrant splicing induced by cancer-associated SF3B1 mutation, and reveal an important role of alternative polypyrimidine tract in diseases.

scholarly journals Alternative Splicing of a Novel Glycophorin Allele GPHe(GL) Generates Two Protein Isoforms in the Human Erythrocyte Membrane

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 391-397 ◽  
Author(s):  
Cheng-Han Huang ◽  
Olga O. Blumenfeld ◽  
Marion E. Reid ◽  
Ying Chen ◽  
Geoff L. Daniels ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Splice Site ◽  
Rna Splicing ◽  
Phenotypic Diversity ◽  
Full Length ◽  
Protein Isoforms ◽  
Membrane Domain ◽  
Acceptor Splice Site ◽  
Variable Expression ◽  
Aberrant Rna

Abstract The Henshaw antigen (synonym: He or MNS6) is carried by an altered form of glycophorin B (GPB), but the molecular basis for its variable expression or quantitative polymorphism remains largely undefined. We report here the identification and analysis of a novel glycophorin He allele, GPHe(GL), which gives rise to the expression of two protein isoforms in the erythrocyte membrane. In addition to the nucleotide changes defining the epitopic sequence of He, a single C-to-G nucleotide transversion in exon V coding for the membrane domain was found to cause aberrant RNA splicings by creating a new acceptor splice site. In addition, a T-to-G transversion at −6 position of the acceptor splice site for exon IV was identified. Both full-length and truncated transcripts of GPHe(GL) were detected as the result of partial activation of the new acceptor splice site and partial inactivation of the normal splice sites. The full-length cDNA encoded He, S, and U antigens, whereas the three truncated ones lacked either the sequence for S and U antigens or a large portion of the membrane domain or both. The GPB gene on the other chromosome was apparently normal and its transcript encoded N, s, and U antigens. These results correlate alternative RNA splicing with the expression of two GPHe isoforms and thus delineate a new mechanism for the phenotypic diversity of membrane glycophorins.

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 130
Author(s):  
Flavia Zita Francies ◽  
Sheynaz Bassa ◽  
Aristotelis Chatziioannou ◽  
Andreas Martin Kaufmann ◽  
Zodwa Dlamini
Keyword(s):  
Cervical Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Molecular Alteration ◽  
Common Cancer ◽  
Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

scholarly journals Regulation of RNA Splicing: Aberrant Splicing Regulation and Therapeutic Targets in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 923
Author(s):  
Koji Kitamura ◽  
Keisuke Nimura
Keyword(s):  
Dna Sequences ◽  
Rna Splicing ◽  
Splicing Factors ◽  
Splicing Regulation ◽  
Aberrant Splicing ◽  
Aberrant Expression ◽  
Non Coding Rnas ◽  
Precursor Mrna ◽  
Splicing Enhancer ◽  
Small Nuclear Ribonucleoproteins

RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA) by removing introns and exons. The combination of inclusion and exclusion of introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a limited number of genes. Cancer cells acquire cancer-specific mechanisms through aberrant splicing regulation to acquire resistance to treatment and to promote malignancy. Splicing regulation involves many factors, such as proteins, non-coding RNAs, and DNA sequences at many steps. Thus, the dysregulation of splicing is caused by many factors, including mutations in RNA splicing factors, aberrant expression levels of RNA splicing factors, small nuclear ribonucleoproteins biogenesis, mutations in snRNA, or genomic sequences that are involved in the regulation of splicing, such as 5’ and 3’ splice sites, branch point site, splicing enhancer/silencer, and changes in the chromatin status that affect the splicing profile. This review focuses on the dysregulation of RNA splicing related to cancer and the associated therapeutic methods.

scholarly journals MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 39
Author(s):  
Crescenzo Massaro ◽  
Elham Safadeh ◽  
Giulia Sgueglia ◽  
Hendrik G. Stunnenberg ◽  
Lucia Altucci ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Hormone Signaling ◽  
Cancer Resistance ◽  
Comprehensive Overview ◽  
Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

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