Splicing factors: Insights into their regulatory network in alternative splicing in cancer

AbstractBackgroundNonsense mediated mRNA decay (NMD) is an RNA surveillance pathway that degrades aberrant transcripts harboring premature termination codons. This pathway, in conjunction with alternative splicing, regulates gene expression post-transcriptionally. Nearly all serine and arginine-rich (SR) proteins and many heterogeneous nuclear ribonucleoproteins (hnRNPs) produce isoforms that can be degraded by the NMD pathway. Many splicing factors have been reported to be regulated via alternative splicing coupled to NMD. However, it is still uncharacterized that to what extent NMD contributes to the regulation of splicing factors.ResultsHere, we characterized a regulatory network of splicing factors through alternative splicing coupled to NMD. Based upon an extensive literature search, we first assembled a network that encompasses the current knowledge of splice factors repressing or activating the expression of other splicing factors through alternative splicing coupled to NMD. This regulatory network is limited, including just a handful of well-studied splicing factors. To gain a more global and less biased overview, we examined the splicing factor-mRNA interactions from public crosslinking-immunoprecipitation (CLIP)-seq data, which provides information about protein–RNA interactions. A network view of these interactions reveals extensive binding among splicing regulators. We also found that splicing factors bind more frequently to transcripts of other splicing factors than to other genes. In addition, many splicing factors are targets of NMD, and might be regulated via alternative splicing coupled to NMD, which is demonstrated by the significant overlap between the experimental network and eCLIP-network. We found that hierarchy of the splicing-factor interaction network differs from the hierarchy observed for transcription factors.ConclusionThe extensive interaction between splicing factors and transcripts of other splicing factors suggests that the potential regulation via alternative splicing coupled with NMD is widespread. The splicing factor regulation is fundamentally different from that of transcription factors.

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Prognostic Signature of Alternative Splicing Events in Bladder Urothelial Carcinoma Based on Spliceseq Data from 317 Cases

Cellular Physiology and Biochemistry ◽

10.1159/000492094 ◽

2018 ◽

Vol 48 (3) ◽

pp. 1355-1368 ◽

Cited By ~ 26

Author(s):

Rong-quan He ◽

Xian-guo Zhou ◽

Qiao-yong Yi ◽

Cai-wang Deng ◽

Jia-min Gao ◽

...

Keyword(s):

Alternative Splicing ◽

Urothelial Carcinoma ◽

Risk Score ◽

Regulatory Network ◽

Pearson Correlation ◽

Risk Scores ◽

Pathway Enrichment Analysis ◽

Splicing Factors ◽

Bladder Urothelial Carcinoma ◽

Alternative Splicing Events

Background/Aims: Increasing evidences indicated the important roles of alternative splicing in the progression and prognosis of bladder urothelial carcinoma (BLCA). However, most previous research has focused on one or several alternative splicing events, without a comprehensive evaluation of the prognostic value of splicing events in BLCA. In this study, we aimed to determine risk scores for predicting prognosis of BLCA patients based on splicing events. Methods: RNA-sequencing data and clinical information of BLCA patients were downloaded from The Cancer Genome Atlas, and data of splicing events were obtained from the SpliceSeq database. Univariate and multivariate Cox regression analyses were employed to identify survival-associated alternative spicing events (SASEs) and to calculate risk scores. Protein-protein interaction analysis of genes of the SASEs was performed using STRING, a database of known and predicted protein-protein interactions, and pathway enrichment analysis of the genes was implemented using the Database for Annotation, Visualization and Integrated Discovery (version 6.8). Receiver operating characteristic (ROC) curves and Kaplan-Meier analysis were used to evaluate the clinical significance of genes from the SASEs for building a risk score in BLCA. Correlation between splicing events of splicing factors and non-splicing factors were analyzed with Pearson correlation coefficient. A potential regulatory network was then built using Cytoscape 3.5. Results: In total, 39,508 alternative splicing events in 317 patients with BLCA were analyzed, including 4,632 SASEs. The area under the curve of the ROC of risk score (all) was 0.748 for predicting survival status of BLCA patients. Low- and high-risk score groups classified using the median “risk score (all)” value displayed remarkably different survival time (Low vs. High = 3304.841±239.758 vs 1198.614±152.460 days). The potential regulatory network with SASEs of splicing factors and other genes was constructed, which might be part of the biological mechanisms associated with prognosis of BLCA patients. Conclusions: In this study, prognostic signatures constructed using splicing events could be used for predicting the prognosis of BLCA patients.

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

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)50549-x ◽

1992 ◽

Vol 267 (10) ◽

pp. 7139-7147

Author(s):

D.M. Rothstein ◽

H Saito ◽

M Streuli ◽

S.F. Schlossman ◽

C Morimoto

Keyword(s):

Alternative Splicing ◽

Tyrosine Phosphatase ◽

Splicing Factors

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Alternative splicing acts as an independent prognosticator in ovarian carcinoma

Scientific Reports ◽

10.1038/s41598-021-89778-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yan Ouyang ◽

Kaide Xia ◽

Xue Yang ◽

Shichao Zhang ◽

Li Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Regression Analysis ◽

Alternative Splicing ◽

Ovarian Carcinoma ◽

Cancer Patients ◽

Cox Regression ◽

Excision Repair ◽

Splicing Factors ◽

Prognostic Signature ◽

Cox Regression Analysis

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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