The alternative splicing of the CD45 tyrosine phosphatase is controlled by negative regulatory trans-acting splicing factors.

AbstractAlternative splicing (AS) events associated with oncogenic processes present anomalous perturbations in many cancers, including ovarian carcinoma. There are no reliable features to predict survival outcomes for ovarian cancer patients. In this study, comprehensive profiling of AS events was conducted by integrating AS data and clinical information of ovarian serous cystadenocarcinoma (OV). Survival-related AS events were identified by Univariate Cox regression analysis. Then, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to construct the prognostic signatures within each AS type. Furthermore, we established a splicing-related network to reveal the potential regulatory mechanisms between splicing factors and candidate AS events. A total of 730 AS events were identified as survival-associated splicing events, and the final prognostic signature based on all seven types of AS events could serve as an independent prognostic indicator and had powerful efficiency in distinguishing patient outcomes. In addition, survival-related AS events might be involved in tumor-related pathways including base excision repair and pyrimidine metabolism pathways, and some splicing factors might be correlated with prognosis-related AS events, including SPEN, SF3B5, RNPC3, LUC7L3, SRSF11 and PRPF38B. Our study constructs an independent prognostic signature for predicting ovarian cancer patients’ survival outcome and contributes to elucidating the underlying mechanism of AS in tumor development.

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

Genes ◽

10.3390/genes12020130 ◽

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.

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Trans-acting Factors Required for Inclusion of Regulated Exons in the Ultrabithorax mRNAs of Drosophila melanogaster

Genetics ◽

10.1093/genetics/151.4.1517 ◽

1999 ◽

Vol 151 (4) ◽

pp. 1517-1529 ◽

Cited By ~ 2

Author(s):

James M Burnette ◽

Allyson R Hatton ◽

A Javier Lopez

Keyword(s):

Drosophila Melanogaster ◽

Alternative Splicing ◽

P Element ◽

Splicing Factors ◽

Loss Of Function ◽

Large Collection ◽

Splicing Pattern ◽

Alternatively Spliced ◽

Hypomorphic Alleles

Abstract Alternatively spliced Ultrabithorax mRNAs differ by the presence of internal exons mI and mII. Two approaches were used to identify trans-acting factors required for inclusion of these cassette exons. First, mutations in a set of genes implicated in the control of other alternative splicing decisions were tested for dominant effects on the Ubx alternative splicing pattern. To identify additional genes involved in regulation of Ubx splicing, a large collection of deficiencies was tested first for dominant enhancement of the haploinsufficient Ubx haltere phenotype and second for effects on the splicing pattern. Inclusion of the cassette exons in Ubx mRNAs was reduced strongly in heterozygotes for hypomorphic alleles of hrp48, which encodes a member of the hnRNP A/B family and is implicated in control of P-element splicing. Significant reductions of mI and mII inclusion were also observed in heterozygotes for loss-of-function alleles of virilizer, fl(2)d, and crooked neck. The products of virilizer and fl(2)d are also required for Sxl autoregulation at the level of splicing; crooked neck encodes a protein with structural similarities to yeast-splicing factors Prp39p and Prp42p. Deletion of at least five other loci caused significant reductions in the inclusion of mI and/or mII. Possible roles of identified factors are discussed in the context of the resplicing strategy for generation of alternative Ubx mRNAs.

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Characterization of alternative splicing events and prognostic signatures in breast cancer

BMC Cancer ◽

10.1186/s12885-021-08305-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Pihua Han ◽

Jingjun Zhu ◽

Guang Feng ◽

Zizhang Wang ◽

Yanni Ding

Keyword(s):

Breast Cancer ◽

Alternative Splicing ◽

Proportional Hazards ◽

Pearson Correlation ◽

Original Data ◽

Cox Proportional Hazards ◽

Prognostic Indicators ◽

Splicing Factors ◽

Rna Seq

Abstract Background Breast cancer (BRCA) is one of the most common cancers worldwide. Abnormal alternative splicing (AS) frequently observed in cancers. This study aims to demonstrate AS events and signatures that might serve as prognostic indicators for BRCA. Methods Original data for all seven types of splice events were obtained from TCGA SpliceSeq database. RNA-seq and clinical data of BRCA cohorts were downloaded from TCGA database. Survival-associated AS events in BRCA were analyzed by univariate COX proportional hazards regression model. Prognostic signatures were constructed for prognosis prediction in patients with BRCA based on survival-associated AS events. Pearson correlation analysis was performed to measure the correlation between the expression of splicing factors (SFs) and the percent spliced in (PSI) values of AS events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted to demonstrate pathways in which survival-associated AS event is enriched. Results A total of 45,421 AS events in 21,232 genes were identified. Among them, 1121 AS events in 931 genes significantly correlated with survival for BRCA. The established AS prognostic signatures of seven types could accurately predict BRCA prognosis. The comprehensive AS signature could serve as independent prognostic factor for BRCA. A SF-AS regulatory network was therefore established based on the correlation between the expression levels of SFs and PSI values of AS events. Conclusions This study revealed survival-associated AS events and signatures that may help predict the survival outcomes of patients with BRCA. Additionally, the constructed SF-AS networks in BRCA can reveal the underlying regulatory mechanisms in BRCA.

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Genome-wide transcriptome analysis identifies alternative splicing regulatory network and key splicing factors in mouse and human psoriasis

Scientific Reports ◽

10.1038/s41598-018-22284-y ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 13

Author(s):

Jin Li ◽

Peng Yu

Keyword(s):

Alternative Splicing ◽

Transcriptome Analysis ◽

Regulatory Network ◽

Splicing Factors ◽

Genome Wide

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Design of RNA-Binding Proteins: Manipulate Alternative Splicing in Human Cells with Artificial Splicing Factors

Methods in Molecular Biology - RNA-Protein Complexes and Interactions ◽

10.1007/978-1-4939-3591-8_18 ◽

2016 ◽

pp. 227-241 ◽

Cited By ~ 1

Author(s):

Yang Wang ◽

Zefeng Wang

Keyword(s):

Alternative Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Human Cells ◽

Splicing Factors

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ALG-1 Influences Accurate mRNA Splicing Patterns in the Caenorhabditis elegans Intestine and Body Muscle Tissues by Modulating Splicing Factor Activities

Genetics ◽

10.1534/genetics.119.302223 ◽

2019 ◽

Vol 212 (3) ◽

pp. 931-951 ◽

Cited By ~ 3

Author(s):

Kasuen Kotagama ◽

Anna L. Schorr ◽

Hannah S. Steber ◽

Marco Mangone

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Rna Splicing ◽

Specific Gene ◽

Splicing Factors ◽

Tissue Specific ◽

Link Type ◽

Body Muscle ◽

Mirna Targets ◽

Mirna Pathway

MicroRNAs (miRNAs) are known to modulate gene expression, but their activity at the tissue-specific level remains largely uncharacterized. To study their contribution to tissue-specific gene expression, we developed novel tools to profile putative miRNA targets in the Caenorhabditis elegans intestine and body muscle. We validated many previously described interactions and identified ∼3500 novel targets. Many of the candidate miRNA targets curated are known to modulate the functions of their respective tissues. Within our data sets we observed a disparity in the use of miRNA-based gene regulation between the intestine and body muscle. The intestine contained significantly more putative miRNA targets than the body muscle highlighting its transcriptional complexity. We detected an unexpected enrichment of RNA-binding proteins targeted by miRNA in both tissues, with a notable abundance of RNA splicing factors. We developed in vivo genetic tools to validate and further study three RNA splicing factors identified as putative miRNA targets in our study (asd-2, hrp-2, and smu-2), and show that these factors indeed contain functional miRNA regulatory elements in their 3′UTRs that are able to repress their expression in the intestine. In addition, the alternative splicing pattern of their respective downstream targets (unc-60, unc-52, lin-10, and ret-1) is dysregulated when the miRNA pathway is disrupted. A reannotation of the transcriptome data in C. elegans strains that are deficient in the miRNA pathway from past studies supports and expands on our results. This study highlights an unexpected role for miRNAs in modulating tissue-specific gene isoforms, where post-transcriptional regulation of RNA splicing factors associates with tissue-specific alternative splicing.

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Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment

Cells ◽

10.3390/cells9020328 ◽

2020 ◽

Vol 9 (2) ◽

pp. 328 ◽

Cited By ~ 4

Author(s):

Ramona Palombo ◽

Veronica Verdile ◽

Maria Paola Paronetto

Keyword(s):

Alternative Splicing ◽

Ewing Sarcoma ◽

Splicing Factors ◽

Mrna Variants ◽

Aggressive Tumor ◽

Chemotherapeutic Treatment ◽

Sarcoma Cells ◽

Combinatorial Mechanism ◽

Worse Prognosis

Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes. Defects in alternative splicing regulation are associated with several human diseases, including cancer. Ewing sarcoma is an aggressive tumor of bone and soft tissue, mainly affecting adolescents and young adults. DHX9 is a key player in Ewing sarcoma malignancy, and its expression correlates with worse prognosis in patients. In this study, by screening a library of siRNAs, we have identified splicing factors that regulate the alternative inclusion of a poison exon in DHX9 mRNA, leading to its downregulation. In particular, we found that hnRNPM and SRSF3 bind in vivo to this poison exon and suppress its inclusion. Notably, DHX9 expression correlates with that of SRSF3 and hnRNPM in Ewing sarcoma patients. Furthermore, downregulation of SRSF3 or hnRNPM inhibited DHX9 expression and Ewing sarcoma cell proliferation, while sensitizing cells to chemotherapeutic treatment. Hence, our study suggests that inhibition of hnRNPM and SRSF3 expression or activity could be exploited as a therapeutic tool to enhance the efficacy of chemotherapy in Ewing sarcoma.

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