Splicing programs and cancer

Abstract

Numerous studies report splicing alterations in a multitude of cancers by using gene-by-gene analysis. However, understanding of the role of alternative splicing in cancer is now reaching a new level, thanks to the use of novel technologies allowing the analysis of splicing at a large-scale level. Genome-wide analyses of alternative splicing indicate that splicing alterations can affect the products of gene networks involved in key cellular programs. In addition, many splicing variants identified as being misregulated in cancer are expressed in normal tissues. These observations suggest that splicing programs contribute to specific cellular programs that are altered during cancer initiation and progression. Supporting this model, recent studies have identified splicing factors controlling cancer-associated splicing programs. The characterization of splicing programs and their regulation by splicing factors will allow a better understanding of the genetic mechanisms involved in cancer initiation and progression and the development of new therapeutic targets.

Figure 1

Genes are an assemblage of exons that can be differentially selected through the use of alternative promoters (P), alternative polyadenylation sites (pA), and alternatively spliced exons.

Figure 2

Tumor cells are able to adapt and to evolve. Tumor cells that proliferate develop mechanisms to escape apoptosis and control of their environment. Some tumor cells stimulate angiogenesis or degrade the extracellular matrix, migrate and colonize other tissues to form metastasis.

Figure 3

Cellular programs depend on gene expression programs that result from both transcriptional and splicing programs. Transcriptional and splicing programs are under the control of transcription and splicing factors, respectively. Mutations or gene expression alteration of transcription and/or splicing factors can contribute to tumor initiation and progression. The activity of transcription and splicing factors is also under the control of signaling pathways that can be altered in tumor initiation and progression.