Alternative splicing as a biomarker and potential target for drug discovery

Abstract

Alternative splicing is a key process of multi-exonic gene expression during pre-mRNA maturation. In this process, particular exons of a gene will be included within or excluded from the final matured mRNA, and the resulting transcripts generate diverse protein isoforms. Recent evidence demonstrates that approximately 95% of human genes with multiple exons undergo alternative splicing during pre-mRNA maturation. Thus, alternative splicing plays a critical role in physiological processes and cell development programs, and.dysregulation of alternative splicing is highly associated with human diseases, such as cancer, diabetes and neurodegenerative diseases. In this review, we discuss the regulation of alternative splicing, examine the relationship between alternative splicing and human diseases, and describe several approaches that modify alternative splicing, which could aid in human disease diagnosis and therapy.

Transcriptome‐Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer

“…Among the seven types of detected ASEs, AF (alternative first exon) event was the most frequently observed ASE type in HCC, closely followed by SE (skipping exon) events. SE events are supposed to be the most common splicing patterns in the mammalian transcriptome, in part because of the investigated areas that are restricted within intragenic regions and the limits of sequencing technology . With the improvement of high‐throughput RNA‐seq technology and abundant transcript annotation, an increasing number of transcript variants generated from the alternative use of transcription start sites are found to play roles in tumors .…”

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

“…In our in vivo studies, DMTF1β overexpression in mouse mammary driven by the MMTV promoter was sufficient to induce mammary gland hyperplasia and multifocal tumor lesions in mice with a mean latency of 16 months [2]. This is significantly longer than the tumor latency of MMTV-HER2 and MMTV-MYC transgenic mice (about 8 and 10 months, respectively) [82,83]. On the contrary, DMTF1α transgenic mice displayed resistance to HER2 -induced mammary tumor [79].…”

Inhibition of mRNA Maturation by Compounds Which Have a Flavonoid Skeleton

“…Messenger RNA splicing has received much attention recently as it was found to be central for the pathology of numerous diseases especially cancer. Therefore, mRNA splicing inhibition is thought to be an important therapeutic strategy [2,[14][15][16][17][18][19][20][21].…”

“…Several small compounds from natural resources which inhibit mRNA processing have been reported and it was proven that pre-mRNA splicing inhibition is the mechanistic foundation for their action [15,16,19,22]. Spliceostatin A and pladienolide B inhibit mRNA splicing by binding to SF3b, a sub-complex of the U2 small nuclear ribonucleoprotein (U2 snRNA) in the spliceosome [23][24][25].…”