The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Abstract

In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing.

Defective control of pre–messenger RNA splicing in human disease

“…Changes in the nuclear level of regulators, including RBFOX2, hnRNP, and SR proteins, often occur in cancer ( Venables et al, 2009 ; Zhang and Manley, 2013 ). Although these changes frequently produce splice variants that affect cell cycle control, apoptosis, cell motility, and invasion, the molecular mechanisms that lead to these alterations and to specific downstream events that promote cancer remain largely unclear ( Zhang and Manley, 2013 ; Shilo et al, 2015 ). Another way to alter the activity of splicing regulators is through sequestration.…”

Integration of mRNP formation and export

“…An important field of investigation is how dysregulation of splicing can be involved in cancerogenesis [258, 259]. Splicing defects in cancer cells can result from base-pair substitutions in splice sites or in splicing regulatory sequences.…”

Identification of prognostic splicing factors and exploration of their potential regulatory mechanisms in pancreatic adenocarcinoma

“…More importantly, intricate splicing events are orchestrated by a limited number of SFs. Many studies have found links between the turbulences of SFs and the onset and progression of cancers (Cieply & Carstens, 2015;Shilo, Siegfried & Karni, 2015;Silipo, Gautrey & Tyson-Capper, 2015). In PAAD, SFs also exhibit potential effective functions in many ways.…”