Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments. 1. Introduction Alternative splicing is the process by which splice sites in precursor messenger RNAs (pre-mRNAs) are differentially selected and paired to produce multiple mature mRNAs and protein isoforms with distinct structural and functional properties. The first example of alternative splicing was discovered almost 30 years ago, when membrane-bound and secreted antibodies were demonstrated to be encoded by the same gene [1, 2]. Now, we know that alternative splicing is a very accurate, efficient, and extraordinarily flexible process that regulates all major aspects of eukaryotic cell biology. Affecting approximately 94% of human genes [3, 4], it represents the major source of the human proteomic diversity. Regulation of alternative splicing decisions involves the recognition of target sequences in the pre-mRNA by a number of splicing regulatory factors with antagonistic functions such as SR (serine-arginine-rich) and hnRNP (heterogeneous nuclear ribonucleoprotein) protein families [5]. Generally, SR proteins promote exon recognition by binding to exonic or intronic splicing enhancer sequences (ESEs and ISEs, resp.), while hnRNP factors typically interact with exonic or intronic splicing silencers (ESSs and ISEs) inhibiting splice sites recognition. The regulation of alternative splicing has been discussed in several excellent reviews [6–8]. Changes in alternative splicing patterns have an essential role in normal development, differentiation, and in response to physiological stimuli, but aberrant splicing generates variants that contribute to multiple aspects of tumor establishment and progression and in the resistance to therapeutic treatments [5, 9, 10]. Many
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