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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Alterations of pre-mRNA splicing in cancer
Zane Kalnina1, Pawel Zayakin, Karīna Silina
1Biomedical Research and Study Centre, University of Latvia, Ratsupites St 1, LV-1067 Riga, Latvia.
Abstract:
Recent genomewide analyses of alternative splicing (AS) indicate that up to 70% of human genes may have alternative splice forms, suggesting that AS together with various posttranslational modifications plays a major role in the production of proteome complexity. Splice-site selection under normal physiological conditions is regulated in the developmental stage in a tissue type-specific manner by changing the concentrations and the activity of splicing regulatory proteins. Whereas spliceosomal errors resulting in the production of aberrant transcripts rarely occur in normal cells, they seem to be an intrinsic property of cancer cells. Changes in splice-site selection have been observed in various types of cancer and may affect genes implicated in tumor progression (for example, CD44, MDM2, and FHIT) and in susceptibility to cancer (for example, BRCA1 and APC). Splicing defects can arise from inherited or somatic mutations in cis-acting regulatory elements (splice donor, acceptor and branch sites, and exonic and intronic splicing enhancers and silencers) or variations in the composition, concentration, localization, and activity of regulatory proteins. This may lead to altered efficiency of splice-site recognition, resulting in overexpression or down-regulation of certain splice variants, a switch in splice-site usage, or failure to recognize splice sites correctly, resulting in cancer-specific splice forms. At least in some cases, changes in splicing have been shown to play a functionally significant role in tumorigenesis, either by inactivating tumor suppressors or by gain of function of proteins promoting tumor development. Moreover, cancer-specific splicing events may generate novel epitopes that can be recognized by the host's immune system as cancer specific and may serve as targets for immunotherapy. Thus, the identification of cancer-specific splice forms provides a novel source for the discovery of diagnostic or prognostic biomarkers and tumor antigens suitable as targets for therapeutic intervention.
Insights
Alternative splicing (AS) errors are common in cancer cells, leading to altered protein functions and tumor development. Identifying cancer-specific splice forms offers new avenues for cancer diagnostics, prognostics, and immunotherapies.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Alternative splicing (AS) contributes significantly to proteome complexity, with up to 70% of human genes exhibiting alternative splice forms.
- Normal splice-site selection is tightly regulated by splicing regulatory proteins in a tissue-specific manner during development.
- Aberrant splice-site selection, unlike in normal cells, appears to be an intrinsic characteristic of cancer cells.
Purpose of the Study:
- To investigate the role of alternative splicing defects in cancer development and progression.
- To explore the potential of cancer-specific splice forms as diagnostic, prognostic, and therapeutic targets.
Main Methods:
- Genomewide analyses of alternative splicing patterns.
- Identification and characterization of cancer-specific splice variants.
- Analysis of mutations in cis-acting regulatory elements and regulatory protein variations.
- Functional studies on the impact of splicing alterations in tumorigenesis.
Main Results:
- Changes in splice-site selection are observed across various cancer types, affecting genes crucial for tumor progression and susceptibility.
- Splicing defects can result from mutations in regulatory elements or alterations in splicing regulatory proteins, leading to altered splice variant expression.
- Cancer-specific splice forms can inactivate tumor suppressors or confer gain-of-function to proteins promoting tumor development.
- Cancer-specific splicing events can generate novel tumor antigens recognized by the immune system.
Conclusions:
- Alternative splicing defects are integral to cancer biology, influencing tumor initiation and progression.
- Cancer-specific splice forms represent a valuable resource for discovering novel biomarkers for cancer diagnosis and prognosis.
- These splice forms also hold potential as targets for cancer immunotherapy due to the generation of unique tumor epitopes.
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