Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities

SIMPLE SUMMARY: Colorectal cancer is the second leading cause of cancer-related deaths worldwide. The incidence of this cancer continues to rise, especially in developing countries. Alternative splicing is a normal cellular process that results in the generation of proteins with different structures and functions from a single gene. Colorectal cancer can cause dysregulation of alternative splicing processes to promote its development and growth until it spreads. Dysregulated alternative splicing processes have been shown to promote cancer survival by producing proteins that activate genes known to promote cancer development or deactivate those that inhibit cancer development. It is therefore important that dysregulated alternative splicing genes in colorectal cancer are identified for diagnosis and development of treatments that can specifically target these genes in order to stop them from promoting cancer development and progression. ABSTRACT: Colorectal cancer (CRC) ranks as one of the top causes of cancer mortality worldwide and its incidence is on the rise, particularly in low-middle-income countries (LMICs). There are several factors that contribute to the development and progression of CRC. Alternative splicing (AS) was found to be one of the molecular mechanisms underlying the development and progression of CRC. With the advent of genome/transcriptome sequencing and large patient databases, the broad role of aberrant AS in cancer development and progression has become clear. AS affects cancer initiation, proliferation, invasion, and migration. These splicing changes activate oncogenes or deactivate tumor suppressor genes by producing altered amounts of normally functional or new proteins with different, even opposing, functions. Thus, identifying and characterizing CRC-specific alternative splicing events and variants might help in designing new therapeutic splicing disrupter drugs. CRC-specific splicing events can be used as diagnostic and prognostic biomarkers. In this review, alternatively spliced events and their role in CRC development will be discussed. The paper also reviews recent research on alternatively spliced events that might be exploited as prognostic, diagnostic, and targeted therapeutic indicators. Of particular interest is the targeting of protein arginine methyltransferase (PMRT) isoforms for the development of new treatments and diagnostic tools. The potential challenges and limitations in translating these discoveries into clinical practice will also be addressed.