Aberrant Splicing Factor SF3A2 as a Prognostic Biomarker and Therapeutic Target in Colorectal Cancer: Interplay with Immune Infiltration and Natural Product Intervention

Abstract

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. While immunotherapy has revolutionized treatment for distinct subtypes, the majority of metastatic CRC patients with microsatellite stable (MSS) tumors exhibit resistance. Emerging evidence suggests that aberrant Alternative Splicing (AS), regulated by specific splicing factors, plays a critical role in tumor progression and immune evasion.

Methods: This study utilized comprehensive transcriptomic data to analyze the expression and prognostic value of Splicing Factor 3a Subunit 2 (SF3A2) in CRC. We employed differential expression analysis, Kaplan-Meier survival estimates, and immune infiltration profiling via CIBERSORT algorithms. Furthermore, we investigated the potential of natural phytochemicals to modulate pathways associated with splicing-induced inflammation.

Results: Our analysis revealed that SF3A2 is significantly upregulated in CRC tissues compared to normal controls, with overexpression correlating with advanced clinical stage and reduced overall survival. Notably, high SF3A2 expression was associated with a suppressive immune microenvironment, characterized by decreased CD8+ T-cell infiltration and increased regulatory T-cell presence. Functional enrichment analysis indicated a convergence of RNA splicing and inflammatory pathways, including NF-kappaB and MAPK signaling.

Conclusion: SF3A2 serves as a potential prognostic biomarker and therapeutic target in CRC, linking RNA processing defects to immune exclusion. The modulation of these pathways by bioactive natural compounds warrants further investigation as a strategy to enhance immunotherapeutic efficacy.

Keywords:

Colorectal Cancer, SF3A2, Alternative Splicing, Immunotherapy

References

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74(1):12-49.

Li Q, Geng S, Luo H, et al. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther. 2024; 9(1):266.

Yang C, Zhao L, Lin Y, et al. Improving the efficiency of immune checkpoint inhibitors for metastatic pMMR/MSS colorectal cancer: Options and strategies. Crit Rev Oncol Hematol. 2024; 200:104204.

Huo Z, Liu G, Li J. Recent research progress and clinical status of immunotherapy for colorectal cancer. J Adv Res. 2025.

Tao Y, Zhang Q, Wang H, et al. Alternative splicing and related RNA binding proteins in human health and disease. Signal Transduct Target Ther. 2024; 9(1):26.

Sun Y, Hu X. Aberrant alternative splicing in cancer: Splicing events and their regulatory mechanisms. Int J Oncol. 2024; 65(3).

Urbanski LM, Leclair N, Anczuków O. Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA. 2018; 9(4):e1476.

Manabile MA, Hull R, Khanyile R, et al. Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities. Cancers (Basel). 2023; 15(15).

Pellacani C, Bucciarelli E, Renda F, et al. Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation. Elife. 2018; 7.

Sun W, Lu H, Cui S, et al. NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis. Cell Commun Signal. 2023; 21(1):29.

Huang Q, Yao Y, Wang Y, et al. Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury. J Adv Res. 2023.

Liu X, Tao Q, Shen Y, et al. Aspirin eugenol ester ameliorates LPS-induced inflammatory responses in RAW264.7 cells and mice. Front Pharmacol. 2023; 14: 1220780.

Shi Y, Chen J, Li S, et al. Tangeretin suppresses osteoarthritis progression via the Nrf2/NF-kappaB and MAPK/NF-κB signaling pathways. Phytomedicine. 2022; 98: 153928.

Friedman M, McQuistan T, Hendricks JD, et al. Protective effect of dietary tomatine against dibenzo[a,l]pyrene (DBP)-induced liver and stomach tumors in rainbow trout. Mol Nutr Food Res. 2007; 51: 1485-91.

Liu Y, Hu H, Yang R, et al. Current advances in the biosynthesis, metabolism, and transcriptional regulation of α-tomatine in tomato. Plants. 2023; 12.