Coordinated expression of retained introns and poison exons in renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Understanding tumor-specific RNA isoforms in cancer, particularly clear cell renal cell carcinoma (ccRCC), remains challenging.
• The interplay between oncogenic signaling, mRNA processing, and decay pathways is not fully elucidated.

Purpose of the Study:

• To investigate the role of intron retention (IR) and poison exon (PE) inclusion in ccRCC pathogenesis.
• To identify molecular regulators of these RNA processing events and their clinical significance.
• To explore the relationship between RNA isoforms, signaling pathways, and immune infiltration in ccRCC.

Main Methods:

• Transcriptomic analyses (RNA sequencing) were employed to profile ccRCC tumors.
• Experimental validation was performed to confirm findings.
• Analysis of RNA processing events, including intron retention and poison exon inclusion, was conducted.
• Correlation with clinical features, survival data, and immune cell signatures was assessed.

Main Results:

• ccRCC tumors exhibit coordinated intron retention (IR) and poison exon (PE) inclusion, leading to transcripts targeted by nonsense-mediated decay (NMD).
• ccRCC tumors were classified into two subtypes based on IR levels: low IR and high IR, with high IR associated with aggressive clinical features and poorer survival.
• Mammalian target of rapamycin (mTOR) signaling was identified as a key regulator; mTOR inhibition increased NMD-targeted isoforms, linking mTOR to RNA surveillance.
• High IR tumors showed increased T cell infiltration signatures.

Conclusions:

• Aggressive ccRCC tumors utilize a mechanism involving aberrant RNA isoforms generated by coordinated IR and PE inclusion.
• mTOR signaling plays a crucial role in modulating these RNA processing events and RNA surveillance pathways.
• These findings provide insights into potential biomarkers and therapeutic targets for ccRCC, highlighting the link between RNA processing, signaling, and the tumor immune microenvironment.