Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epidemiology in High-Income Countries Versus Sub-Saharan Africa
3. Alternative Splicing as a Highly Regulated Process
4. Clinical Significance of AS Events in Cancer
5. Alternative Splicing (AS) Events in Colorectal Cancer Pathogenesis
5.1. Implications of lncRNAs AS Events in Colorectal Cancer
5.2. Other AS Variants Associated with Colorectal Cancer
6. Contribution of PRMTs and SFKs Regulatory Networks in CRC Carcinogenesis
6.1. The Role of Alternatively Spliced Transcripts of PRMTs in Colorectal Cancer
6.2. The Role of VEGF in CRC and Metastasis
7. Therapeutic Potential of Splicing Disrupter Drugs in Cancer and Colorectal Cancer
8. Limitations and Challenges of Using AS in a Clinical Setting
9. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene(s) of Interest | Splicing Regulator | Spliced Events | Type of Marker | Description | Ref. |
---|---|---|---|---|---|
CCND1 | SRSF1 | G/A polymorphism at exon 4 and intron 4 | Prognostic | Upregulated and promotes cell-cycle and cell proliferation via tumour suppressor protein Rb | [9] |
VCL, TPM1, and CALD1 | SF3B4 | 45,439 AS events, predominantly exon Skipping event | Prognostic | Upregulated and associated with patient survival. | [24,26] |
CDK10, TP53, MAP4K3, and ERBB2IP | DNA-directed RNA polymerase II and the RNA spliceosomal complex | 2589 alternative splicing events where ES occurrences predominated as the most common | Prognostic | Contribute to the development and spread of cancer | [27] |
MAPKBP1 | N/I | 60,754 AS events. ES was the most predominant AS event | Prognostic | Six mRNA splice variant prognostic models were significantly associated with the OS. | [28] |
PAR3 and NUMB | TDP43/SRSF3 complex | A total of 45,421 splice events were detected. | prognosis, relapse, and metastasis | Upregulation of TDP43 associated with poor prognosis | [29] |
NFIC/CTF5 | MCPIP1 | A total of 762 AS events were detected | cell cycle progression and proliferation | Increased levels of MCPIP1 were correlated with prolonged OS | [30] |
TET3, FGFR2, p120-Catenin and CD44 | ESRP1 | Exon 2 and 3 skipping in p120-catenin. Cassette exon in CD44 | Diagnostic | Upregulated and plays a central role in epithelial to mesenchymal transition. Increased expression of CD44s. | [31,32,33,34] |
Gene | Splicing Event | Variant/ Isoform | Biological Function | Type of Cancer | Ref. |
---|---|---|---|---|---|
Angiogenesis | |||||
VEGFA | Alternative 3′ splice site in exon 8 | VEGF165 | promote cell growth and migration, proangiogenic | Colorectal, skin, prostate, and renal cancer | [11,50,51,52] |
VEGFR | Intron 13 retention | mVEGFR-2 | Proangiogenic and lymphangiogenic | Colon cancer, colorectal neoplasms | [53,54,55] |
Apoptosis | |||||
MNK2 | Inclusion of exon 14b and skipping of exon 14a | MNK2b | Increased cell-growth and decreased cellular apoptosis (Pro-oncogenic) | Colorectal, breast, and lung cancer | [11,46,55,56] |
BCL2L1 | 5′ alternative splice site usage in exon 2 | BCL-xl | Inhibits- or Anti-apoptotic | Colorectal, lymphoma, prostate, and breast cancer | [37,43,57] |
PKM | Skipping of exon 9 and inclusion of exon 10 | PKM2 | Cell-proliferation, tumorigenesis, and anti-apoptotic | Colon, ovarian, gastric, and liver cancer | [45,58,59,60] |
MRPL33 | Inclusion of alternative exon 3 | MRPL33-fl | Promotes cell-growth and anti-apoptotic | Gastric and colon cancers | [61,62] |
Proliferation | |||||
MNK2 | Inclusion of exon 14b and skipping of exon 14a | MNK2b | Increase cell-growth and proliferation | Colorectal, breast, and lung cancers | [47,56] |
CD44 | Contains exon v4-10 | CD44v4-10 | Tumour-cell proliferation | Colon and intestinal cancer | [46,47,61,62,63] |
PKM | Skipping of exon 9 and inclusion of exon 10 | PKM2 | Increase Cell-proliferation | Colon, ovarian, gastric, and liver cancer | [56,57,64] |
DBF4B | Exon 6 retention | BDF4B-FL | Increase cell-proliferation and tumorigenesis | Colon cancer | [65] |
Invasion and Metastasis | |||||
CD44 | Inclusion of variable exon 6 | CD44v6 | Induces cell migration and promotes metastasis | Colon cancer | [66,67,68] |
CAECAM1 | Inclusion of exon 7 | CEACAM1 | Promotes invasion and migration (colon–liver metastasis). Accelerates metastasis and progression | Colorectal cancer, Metastatic melanoma | [69,70,71,72] |
MST1R | Exon 11 skipping | RONΔex11 | Initiates tumour-cell motility and invasion | Ovarian, colon, lung, and gastric cancers | [73,74,75] |
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Share and Cite
Manabile, M.A.; Hull, R.; Khanyile, R.; Molefi, T.; Damane, B.P.; Mongan, N.P.; Bates, D.O.; Dlamini, Z. Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities. Cancers 2023, 15, 3999. https://doi.org/10.3390/cancers15153999
Manabile MA, Hull R, Khanyile R, Molefi T, Damane BP, Mongan NP, Bates DO, Dlamini Z. Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities. Cancers. 2023; 15(15):3999. https://doi.org/10.3390/cancers15153999
Chicago/Turabian StyleManabile, Mosebo Armstrong, Rodney Hull, Richard Khanyile, Thulo Molefi, Botle Precious Damane, Nigel Patrick Mongan, David Owen Bates, and Zodwa Dlamini. 2023. "Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities" Cancers 15, no. 15: 3999. https://doi.org/10.3390/cancers15153999