Dysregulation of mRNA splicing in urothelial carcinoma: Clinical, diagnostic and therapeutic implications

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Alterations in messenger RNA (mRNA) splicing are key drivers of molecular heterogeneity in cancers, including urothelial carcinoma (UC).
• Splicing dysregulation contributes to cancer progression, treatment response, and clinical outcomes in UC.
• These changes stem from mutations in spliceosomal components or alternative splicing of cancer-associated genes.

Purpose of the Study:

• To review the role of pre-mRNA splicing dysregulation in urothelial carcinoma biology.
• To highlight splicing-factor mutations and their prognostic impact in UC.
• To explore emerging spliceosome-targeted therapies for UC.

Main Methods:

• Literature review focusing on mRNA splicing in urothelial carcinoma.
• Examination of splicing alterations affecting cell proliferation, invasion, metastasis, immune microenvironment, metabolism, and therapeutic resistance.
• Discussion of splicing-factor mutations, cancer-specific isoforms, and susceptibility factors.
• Review of novel therapeutic strategies, including splice-switching oligonucleotides and small molecule spliceosome inhibitors.

Main Results:

• Dysregulated splicing significantly influences critical aspects of UC biology, from cell behavior to treatment resistance.
• Frequently observed splicing-factor mutations and aberrant splicing events correlate with prognosis in UC.
• Splicing alterations are implicated in UC susceptibility and therapeutic outcomes.
• Emerging spliceosome-targeting agents show promise for precision medicine in UC.

Conclusions:

• Aberrant mRNA splicing is a fundamental mechanism underlying urothelial carcinoma's molecular diversity and clinical behavior.
• Targeting splicing represents a promising frontier for developing novel, personalized therapeutic strategies for UC patients.