Alternative splicing and cancer: a systematic review

Abstract

The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.

Fig. 1

Spliceosome assembly. U1 snRNP recognizes 5′ SS and binds through base-pairing, SF1 binds to BPS, U2AF2 binds to polypyrimidine tract and U2AF1 binds to 3′ SS, forming Complex E. Next, U2 snRNP, with the assistance of U2AF, replaces SF1 with the BPS through base-pairing to form Complex A. Next, U5/U4/U6 is recruited and results in the rearrangement of Complex A. Among them, U4 and U6 snRNP are combined through complementary pairing of their RNA components, while U5 snRNP is loosely bound through protein interaction, at which time a Complex B is formed. Through a series of conformational changes, U1 snRNP leaves, U6 snRNP binds to 5′ SS, and at the same time, U4 snRNP leaves so that U6 snRNP and U2 snRNP pair through snRNA. After this rearrangement process, Pre-catalytic Spliceosome Complex B is formed, followed by two transesterification reactions. The first transesterification reaction generates Complex C. The rearrangements occur in Complex C, promoting second transesterification, resulting in a post-spliceosomal complex. As a result, exons are interconnected to form mature mRNA, introns are degraded and snRNPs are recycled. SF1 splicing factor 1, BPS branch point sequence, SS splice-site, snRNPs small nuclear RNPs

Fig. 2

The main alternative splicing patterns are divided into five types: exon skipping (also called cassette exon); intron retention; mutually exclusive exons (only some exons appear in mature mRNA); A5SS (the change of the splicing site causes the position of the 3′ end of the exon to change); A3SS (the change of the splicing site causes the position of the 5′ end of the exon to change). SS, splice site; A5SS, alternative SS

Fig. 3

Roles of alternative splicing in tumorigenesis. The diagram illustrates different hallmarks of cancer along with examples of alternative splicing events that contribute to the transformation of normal cells into tumor cells mainly via proliferation and apoptosis, invasion and metastasis, angiogenesis and metabolism. Arrows up and down indicate the alternative isoforms contributing the most and the least to each process. ITGA6 integrin subunit α6, PKM pyruvate kinase, Bcl B-cell lymphoma, VEGF vascular endothelial growth factor, TAK1 TGF-β-activated kinase 1, CD44 cluster of differentiation 44

Fig. 4

Oncogenic signal transduction driving alternative splicing in cancer. The RAS/RAF/ERK, PI3K/AKT and Wnt signaling pathways play an important role in regulating splicing factor via transcriptional regulation and/or post-translational modification, which lead to aberrant-splicing events that promote oncogenesis. P phosphorylation, Wnt Wingless, ERK extracellular signal regulated kinase, PI3K phosphatidylinositol 3-kinase

Fig. 5

Modulation of splicing as potential cancer therapeutics. Several representative strategies are depicted in the simplified splicing regulation diagram, including small molecules targeting the core spliceosome SF3b-complex compound, SSOs, ASO, short hairpin RNA interference/small interference RNA, clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) system, single-BEs (CBEs or ABEs) as well as antibodies against tumor-specific neo-antigen due to alternative splicing. SR serine/arginine-rich, ESE exonic splicing enhancer, ESS exonic splicing silencer, ISE intronic splicing enhancer, ISS intronic splicing silencer, SSOs splice-switching antisense oligonucleotides, ASO antisense oligonucleotide, BEs base editors, CBEs cytosine-BEs, ABEs adenine-BEs, CRISPR-Cas clustered regularly interspaced short palindromic repeats-Cas