Function, clinical application, and strategies of Pre-mRNA splicing in cancer

Abstract

Pre-mRNA splicing is a fundamental process that plays a considerable role in generating protein diversity. Pre-mRNA splicing is also the key to the pathology of numerous diseases, especially cancers. In this review, we discuss how aberrant splicing isoforms precisely regulate three basic functional aspects in cancer: proliferation, metastasis and apoptosis. Importantly, clinical function of aberrant splicing isoforms is also discussed, in particular concerning drug resistance and radiosensitivity. Furthermore, this review discusses emerging strategies how to modulate pathologic aberrant splicing isoforms, which are attractive, novel therapeutic agents in cancer. Last we outline current and future directions of isoforms diagnostic methodologies reported so far in cancer. Thus, it is highlighting significance of aberrant splicing isoforms as markers for cancer and as targets for cancer therapy.

Fig. 1

The role of alternative RNA splicing in cancer. The balance between noncancerous isoform (a) and cancerous isoform (b) is an important contributor to cancer genesis. To date, there are particularly two approaches of interfering with the RNA splicing process: the use of SSO and application of appropriately active small molecules

Fig. 2

Schematic representation of different types of RNA splicing. The dotted grey lines indicate the alternative splicing processes: a exon skipping; b, c alternative 3′- and 5′-SS; d mutually exclusive exons; e intron retention; f usage of alternative promoters; g alternative polyadenylation. P promoter, polyA site of polyadenylation

Fig. 3

Schematic representation of AR-v7 mechanism of action in chemoresistance. a AR-FL is composed of an N-terminal domain (NTD), a central DNA-binding domain (DBD), a hinge region (red box), and a C-terminal ligand-binding domain (LBD). AR-v7 transcripts lack the reading frame for the LBD. b it highlights the AR activation axis, with conversion of testosterone to dihydrotestosterone (DHT) by the 5α-reductase enzyme, and subsequent AR activation, dimerisation, nuclear translocation and activation of transcriptional activation of target genes expression. c AR-v7 is characterised by loss of the LBD, often resulting in testosterone-independent activation of target genes expression. d morpholino technology caused a splice switch that inhibited expression of AR-v7 and blocked testosterone -independent growth of CRPC cells

Fig. 4

Schematic representation of p73 mechanism of action in radiosensitivity. The ratio of TAp73/ΔNp73 could be considered a potential molecular switch, regulating Bax/Bcl-2 ratio, and preventing cytochrome c release and caspase activation, and enabling sensitisation of cancer cells to radiation

Fig. 5

Splicing-switch oligonucleotides (SSOs) as a means to modulate RNA splicing. a An SSO that binds to an intronic splicing silencer (ISS) prevents binding of a negative splicing factor (orange), leading to exon inclusion. b An SSO that binds to an exonic splicing enhancer (ESE) blocks the binding of the stimulatory splicing factor (mustard), resulting in exon skipping