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A Functional Network of Gastric-Cancer-Associated Splicing Events Controlled by Dysregulated Splicing Factors

ABSTRACT: Except for a few genes known to have oncogenic spliceforms in gastric cancer, the full scope of aberrant splicing in gastric oncogenesis remains unclear. In this study, we elucidated the alternative splicing events associated with gastric carcinogenesis and identified upstream regulators governing these events. We performed RNA-seq on 19 matched tumor/normal pairs and a panel of gastric cancer cell lines, and identified 361 tumor associated (TA) alternative splicing events (ASEs), which included known oncogenic ASEs in genes such as INSR, FGFR2, CD44 and KRAS. We further identified 8 splicing factors dysregulated in gastric tumors, the expression of which are correlated to the splice ratio of the TA ASEs. We thereby constructed a dysregulated splicing network in gastric cancer, consisting of alternative splicing changes correlated to their potential regulators. This network featured three potential regulatory modules centered around the splicing factors ESRP2, MBNL1 and PTPB1. Knockdown of each splicing factor led to the expected changes in splicing of approximately half of the ASEs assayed. Thus, dysregulation of the splicing factors indeed was the cause of many of the TA ASEs. Pathway enrichment analysis showed that genes affected by tumor associated splicing were pre-dominantly involved in cytoskeletal organization. Concordant with this, knockdown of the splicing factors regulating the TA ASEs led to the expected changes in trans-well migration activity. Thus, we have established for the first time a comprehensive splicing network that likely drives gastric tumor progression, based on which novel therapeutic targets can be identified for further evaluation.

PROVIDER: EGAS00001002256 | EGA |

REPOSITORIES: EGA

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A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors

Project description:A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors

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Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

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2016-03-14 | E-GEOD-79157 | biostudies-arrayexpress

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

2016-03-14 | GSE79157 | GEO

Insights into transcriptome surveillance and alternative splicing regulation by the EJC-associated splicing factor RNPS1

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The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

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2010-08-18 | E-GEOD-17468 | biostudies-arrayexpress

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Project description:Abstract: Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP protein SmB/B’ self-regulates its expression by promoting the inclusion of a highly-conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B’ in human cells results in reduced levels of snRNPs and in a striking reduction in the inclusion levels of hundreds of alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors. HeLa cells were transfected with a control non-targeting siRNA pool (siNT), or with siRNA pools designed to knockdown SmB/B' or SRSF1 (also known as SF2/ASF/SFRS1). Sequence reads were aligned to exon-exon junction sequences in a database of EST/cDNA-mined cassette-type alternative splicing events. Processed data files (.bed and .txt) provided as supplementary files on the Series record. Processed data file build information: hg18.

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Quaking is a global regulator of muscle-specific alternative splicing in vertebrates [siRNA data]

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2013-06-05 | E-GEOD-40961 | biostudies-arrayexpress

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2010-08-23 | GSE22937 | GEO

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