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Alternative RNA splicing and cancer

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Alternative splicing of pre‐messenger RNA (mRNA) is a fundamental mechanism by which a gene can give rise to multiple distinct mRNA transcripts, yielding protein isoforms with different, even opposing, functions. With the recognition that alternative splicing occurs in nearly all human genes, its relationship with cancer‐associated pathways has emerged as a rapidly growing field. In this review, we summarize recent findings that have implicated the critical role of alternative splicing in cancer and discuss current understandings of the mechanisms underlying dysregulated alternative splicing in cancer cells. WIREs RNA 2013, 4:547–566. doi: 10.1002/wrna.1178 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease

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Schematics of different modes of alternative splicing. Exons are denoted as boxes and introns are depicted as thin lines in black.
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The PKM2 splice isoform is aberrantly upregulated in tumor cells for a metabolic switch favoring biosynthesis. Mutually exclusive exon splicing of exon 9 (yellow) and exon 10 (magenta) of the PKM pre‐mRNA (messenger RNA) gives rise to two protein isoforms PKM1 and PKM2, respectively. PKM1 is highly efficient in converting PEP (phosphoenolpyruvate) to pyruvate, allowing cells for maximal energy production through the TCA cycle. PKM2, on the other hand, has low efficiency in PEP–pyruvate conversion. Cells that express high levels of PKM2 undergo aerobic glycolysis, fulfilling the need of biosynthesis in embryonic or tumor cells. Splicing factors PTB (polypyrimidine tract‐binding protein) and hnRNP A1/A2 repress exon 9 inclusion by binding to ISS (intronic splicing silencer) elements (red) that flank exon 9, thus promoting the production of PKM2. The cMyc oncogene upregulates the expression of hnRNP A1/A2 in tumor cells.
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CD44 splice isoform switching is critical for EMT (epithelial–mesenchymal transition) and breast cancer progression. Top panel shows a schematic of EMT that involves the change from a cobble‐stone‐like epithelial phenotype to a spindle‐shaped morphology of mesenchymal cells. EMT can be induced by transcription factors Twist, Snail, or the cytokine TGFβ. Middle panel illustrates that CD44 isoform switching from CD44v in epithelial cells to CD44s in mesenchymal cells occurs during EMT. The switched expression to CD44s, which is inhibited by ESRP1, is critical for cells to undergo EMT and form a more aggressive breast cancer phenotype. The CD44 variable exon‐coding region is shown in magenta.
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VEGF (vascular endothelial growth factor) alternative splicing regulates angiogenesis in tumor cells. VEGF exon 8 contains a proximal 3′ splicing site (PSS) and a distal 3′ splicing site (DSS). Splicing factors SRSF1 and SRSF5 promote the usage of 3′ PSS, generating wild‐type and functional VEGF. By contrast, SRSF2 and SRSF6 facilitate the selection of 3′ DSS, resulting in production of the VEGFb isoform that is antiangiogenic. The activity of SRSF1 is regulated by SRPK1 through phosphorylation. IGF‐1 (insulin‐like growth factor 1) promotes SRPK1‐mediated SRSF1 activity and WT1 inhibits the transcription of SRPK1, thus usage of 3′ PSS and the production of VEGF.
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Alternative splicing of the death receptor FAS controls the degree of apoptosis. Usage of the FAS variable exon 6, shown in yellow, is controlled by splicing factors as shown. Inclusion of exon 6 results in a membrane‐bound form of FAS that promotes apoptosis. This inclusion event is mediated by TIA‐1 (T‐cell intracellular antigen 1) and TIAR (TIA‐1‐related) binding at an ESE (exonic splicing enhancer) motif downstream of exon 6 that facilitates U1 snRNP recognition to the 5′ splice site and U2AF binding to the upstream 3′ splice site. In contrast to the membrane‐bound form, exon 6 exclusion produces a soluble form of FAS that inhibits apoptosis. PTB (polypyrimidine tract‐binding protein), RBM5, hnRNPC1/C3, and HuR prevent exon 6 inclusion through binding to exon 6 cis‐elements or preventing the spliceosome assembly. An ESS (exonic splicing silencer) of exon 6 that recruits PTB is shown in red.
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A positive feedback loop couples CD44 alternative splicing and Ras/MAPK activation. A schematic of the CD44 pre‐mRNA is shown with constitutive and variable exons depicted as gray and magenta boxes, respectively. Introns are shown as thin lines. Inclusion of one or more of the variable exons produces CD44v. A human CD44 variant containing variable exons v3 to v10 is frequently detected in CD44v‐expressing cells and is shown to represent CD44v. Variable exon v6‐containing CD44v activates Ras/MAPK signaling by forming a coreceptor complex with RTK. Activation of the Ras/MAPK signaling cascade in turn stimulates the production of CD44v isoforms through splicing factors, Sam68 and SRM160. These actions form a positive feedback loop that sustains Ras/MAPK signaling, critical for tumor cell proliferation. By contrast, the CD44s isoform that is devoid of all variable exons promotes cell contact inhibition.
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Alternative splicing occurs in every category of cancer hallmarks. Examples of genes whose alternative splicing controls a cancer phenotype are shown next to their corresponding hallmarks.
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A schematic representation of alternative splicing regulation. Three core splicing sequences are recognized by components of the spliceosomes: U1 binds to a 5′ splice site (5′ss) that contains a GU dinucleotide. U2AF binds to a 3′ splice site (3′ss) that contains an AG dinucleotide. U2 snRNP binds to a branch site, where adenosine is indicated. ESE and ESS denote exonic splicing enhancer and silencer, respectively. ISE and ISS represent intronic splicing enhancer and silencer, respectively. Splicing activators and repressors bind to these cis‐acting elements for alternative splicing regulation.
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RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease

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