Introduction
Genes are transcribed into pre-mRNA and pass through splicing as a post-transcriptional modification to generate mature mRNA for translation [1]. Splicing is an essential process for gene expression in eukaryotes, eliminating introns and joining the exons, which occurs in the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs) and other proteins [2]. This splicing can generate alternative spliced transcripts from pre-mRNA and different exon constitutions, resulting in different proteins. Alternative splicing can occur in different ways. The most representative mechanisms are as follows: 1, extending or shortening the exon by alternative donor and acceptor sites; 2, exon skipping; 3, mutual exon exclusion; and 4, intron retention [1, 3, 4]. These mechanisms allow protein isoforms with different biological characters to be produced from single genes [1]. Therefore, complex transcriptomes and proteomes could be derived from a limited number of genes [4]. Namely, this process is an important strategy for the complicated regulation of eukaryotes, and most genes (92-95%) undergo this process [5, 6].
Alternative splicing is regulated according to cell type, developmental stage, and disease states [1, 7, 8]. Biochemical mechanisms for the recognition of splice sites are not understood clearly according to cellular conditions, but some tissue-specific factors participate in alternative splicing [4]. In addition, quantitative gene expression is controlled by nonsense-mediated decay mechanisms that degrade targeting mRNAs, producing nonsense mutations. Thus, truncated or erroneous proteins with abnormal functions are prevented from being expressed [9]. Alternative transcripts could be related to various diseases, including cancer. As many as 50% of genetic diseases of humans are related to mutations in splice site sequences and regulatory elements, such enhancers and silencers, resulting in alternative exon constitution [3, 10, 11]. Recently, the SpliceDisease database, providing information for relationships among gene mutation, splicing defects, and diseases, was reported [12]. Especially, aberrent spliced variants are found frequently in cancer, indicating that they could play a role for the survival of cancer cells [8]. Alternative splicing of cancer-related genes could affect cell cycle control, signal transduction pathways, apoptosis, angiogenesis, invasion, and metastasis [8, 13].
Cancer markers allow us to determine the prognosis and therapy for cancer during the remedy of cancer. Thus, the identification of cancer markers is highlighted in the cancer research field [14]. Cancers result from the accumulation of complex genetic and epigenetic alterations against normal regulation. Cancerous cells grow irregularly, create malignant tumors, and move to the other parts of the body. Their alternative spliced transcripts could be detected with cryptic splicing sites. Accordingly, alternative transcripts produced by splicing events represent good candidates for cancer biomarkers [7, 8, 13]. In the present review, we summarize and discuss the alternative splicing events and their potential as cancer biomarkers.