Alternative pre-mRNA processing in cancer progression: clinical significance and therapeutic implications

Abstract: Alternative pre-mRNA processing is a fundamental step in the regulation of gene expression in eukaryotic cells. The combinatorial assortment of exons in the coding sequence, as well as in the untranslated regions, determines in time and space when a specific protein isoform becomes available to the cell, thus allowing fine regulation of gene expression and expansion of the coding potential of the genome. Alternative splicing errors, generated by mutations in cis-acting regulatory elements or in genes encoding splicing factors, dramatically alter gene regulatory networks and contribute to the combined disruption of tumor suppressor genes and activation of oncogenes, thus causing pathological consequences driving the malignant phenotype. In this regard, recent studies have highlighted that changes in splicing fidelity contribute to every aspect of cancer cell biology. This plastic nature of splicing regulation is emerged as promising source of novel and more specific diagnostic and prognostic markers for human cancer. Notably, its potential for anti-cancer therapy is shown by several clinical trials of splicing regulatory drugs. In this review, we discuss the current molecular understanding of the alternative splicing alterations contributing to oncogenic transformation and the resistance to traditional chemotherapeutic treatments. The abnormal expression of splicing factors and their regulators will be reviewed in detail. Finally, novel therapeutic approaches that take advantage of antisense oligonucleotides (ASOs) and small molecules able to bind spliceosomal components and splicing regulators will be also discussed.