Cancer-Associated Perturbations in Alternative Pre-messenger RNA Splicing

Abstract

For most of our 25,000 genes, the removal of introns by pre-messenger RNA (pre-mRNA) splicing represents an essential step toward the production of functional messenger RNAs (mRNAs). Alternative splicing of a single pre-mRNA results in the production of different mRNAs. Although complex organisms use alternative splicing to expand protein function and phenotypic diversity, patterns of alternative splicing are often altered in cancer cells. Alternative splicing contributes to tumorigenesis by producing splice isoforms that can stimulate cell proliferation and cell migration or induce resistance to apoptosis and anticancer agents. Cancer-specific changes in splicing profiles can occur through mutations that are affecting splice sites and splicing control elements, and also by alterations in the expression of proteins that control splicing decisions. Recent progress in global approaches that interrogate splicing diversity should help to obtain specific splicing signatures for cancer types. The development of innovative approaches for annotating and reprogramming splicing events will more fully establish the essential contribution of alternative splicing to the biology of cancer and will hopefully provide novel targets and anticancer strategies. Metazoan genes are usually made up of several exons interrupted by introns. The introns are removed from the pre-mRNA by RNA splicing. In conjunction with other maturation steps, such as capping and polyadenylation, the spliced mRNA is then transported to the cytoplasm to be translated into a functional protein. The basic mechanism of splicing requires accurate recognition of each extremity of each intron by the spliceosome. Introns are identified by the binding of U1 snRNP to the 5' splice site and the U2AF65/U2AF35 complex to the 3' splice site. Following these interactions, other proteins and snRNPs are recruited to generate the complete spliceosomal complex needed to excise the intron. While many introns are constitutively removed by the spliceosome, other splice junctions are not used systematically, generating the phenomenon of alternative splicing. Alternative splicing is therefore the process by which a single species of pre-mRNA can be matured to produce different mRNA molecules (Fig. 1). Depending on the number and types of alternative splicing events, a pre-mRNA can generate from two to several thousands different mRNAs leading to the production of a corresponding number of proteins. It is now believed that the expression of at least 70 % of human genes is subjected to alternative splicing, implying an enormous contribution to proteomic diversity, and by extension, to the development and the evolution of complex animals. Defects in splicing have been associated with human diseases (Caceres and Kornblihtt, Trends Genet 18(4):186-93, 2002, Cartegni et al., Nat Rev Genet 3(4):285-98, 2002, Pagani and Baralle, Nat Rev Genet 5(5):389-96, 2004), including cancer (Brinkman, Clin Biochem 37(7):584-94, 2004, Venables, Bioessays 28(4):378-86, 2006, Srebrow and Kornblihtt, J ...

Neuronal SH-SY5Y cells use the C-dystrophin promoter coupled with exon 78 skipping and display multiple patterns of alternative splicing including two intronic insertion events

“…It has been reported that cancer cells show many alternative splicing events associated with progression, metastasis, and deregulation of splicing factors (Oltean and Bates 2013;Shkreta et al 2013). However, there have been few studies on splicing in the cancer-derived SH-SY5Y cells (Lannaccone et al 2013;Mikulak et al 2012;Saint Martin et al 2012).…”

Quantitative profiling of the UGT transcriptome in human drug-metabolizing tissues

“…Many cancer-related genes are regulated by AS, with the encoded proteins often involved in all major aspects of cancer cell biology. 31 The diversity and abundance of alternative UGT variants are suggestive of a physiological role, possibly in the control of coordinate cellular responses induced by small molecules and in determining exposure to xenobiotics. Given that several alternative variants are expressed at "biologically significant" levels (> 20 FPKM) 23 and some in the context of low canonical expression, alternative functions independent of UGT enzymes may be anticipated.…”

Mechanism of alternative splicing and its regulation

“…A changed efficiency of splice site recognition is the immediate consequence, while irregularities in protein isoforms in different systems ultimately establish the disease state. Any of these alterations affecting alternative splicing can facilitate the appearance of characteristics in cancer cells, including the inappropriate proliferation, migration, methylation changes and resistance to apoptosis and chemotherapy (70). Alternative splicing has been implicated in nearly all aspects of cancer development, and therefore, is a main participant in the disease.…”