Alternative pre-mRNA splicing in digestive tract malignancy

Alternative precursor messenger RNA (pre-mRNA) splicing plays an important role in the generation of functional diversity of the genome. The process of pre-mRNA splicing is regulated by cis- and trans-elements, and their deregulations result in aberrantly spliced individual variants and aberrant expression profiles. Accumulating evidence has revealed that aberrant splicing contributes to a number of diseases including human neoplasms. It is well known that germ line mutations in the cis-element of tumor suppressor genes such as mismatch repair (MMR) genes, the adenomatous polyposis coli (APC) gene and the E-cadherin (CDH1) gene are involved in Lynch syndrome, familial adenomatous polyposis and hereditary diffuse gastric cancer, respectively. In addition, somatic mutations in cis-elements also play a role in tumorigenesis. These genetic alterations including nonsense, missense or silent mutations in cis-elements led to aberrant transcripts by exon skipping, retention of the intron or introduction of a new splice site. The majority of erroneous transcripts with a premature termination codon are eliminated through nonsense-mediated mRNA decay. However, it is difficult to accurately predict the resulting transcripts with current in silico strategies. Correct interpretation of genetic alterations and the investigation of aberrant transcripts are crucial for genetic diagnosis of hereditary diseases and elucidation of the molecular characteristics of neoplasms from a clinical point of view. In this review we summarize the current knowledge of the regulatory mechanism underlying alternative pre-mRNA splicing and aberrant splicing, with particular focus on digestive tract malignancies.