Alterations of pre‐mRNA splicing in cancer

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.

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

“…Accumulating evidence has shown that alternative splicing is associated with cancer (Venables, 2004;Kalnina et al, 2005), and it also represents a novel mechanism for the inactivation of tumor suppressor genes (Huiping et al, 2002;Kaufmann et al, 2002). Alternative splicing also has been described for ING genes.…”

Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

“…In contrast to the difference in expression level, alternative splicing yields functionally distinct protein variants and may drastically alter cellular functions. Increasing evidence suggested that a large number of altered alternatively spliced mRNAs are associated with tumors, and aberrant alternative splicing is a hallmark of cancer cells (Kalnina et al, 2005). A recent report on an RRMcontaining splicing regulator HuD showed that amplification of the N-myc oncogene is controlled by HuD expression levels in neuroblastoma cells (Grandinetti et al, 2006).…”

“…The oncogenic domains of EWS fusion proteins are essential for tumorigenesis (Zinszner et al, 1994;Sorensen and Triche, 1996;Kim and Pelletier, 1999) and deregulate cell differentiation through altered alternative splicing (Yang et al, 2000). As aberrant alternative splicing is an intrinsic property for cancer cells (Kalnina et al, 2005), this phenomenon suggests that CoAA and EWS might have overlapping splicing functions in tumorigenesis.…”

Association analysis of formyl peptide receptor 2 (FPR2) polymorphisms and Aspirin exacerbated respiratory diseases

“…It is well known that intronic SNPs can affect transcript processing through alternative splicing or producing RNA secondary structure. [32][33][34] The FPR2 À4209T4G located in the second intron. Therefore, we have checked the presence of alternatively spliced forms of FPR2 by RT-PCR over exon 1 to exon 3.…”