Antisense oligonucleotide-mediated TRA2β poison exon inclusion induces the expression of a lncRNA with anti-tumor...

Area of Science:

• Molecular Biology
• Cancer Biology
• RNA Splicing

Background:

• Upregulated oncogenic splicing factor TRA2β is linked to human tumors.
• Decreased inclusion of TRA2β's autoregulatory non-coding poison exon (PE) contributes to TRA2β overexpression.
• Low TRA2β-PE inclusion correlates with reduced patient survival in various cancers.

Purpose of the Study:

• To investigate the therapeutic potential of targeting TRA2β-PE inclusion.
• To explore the mechanisms by which TRA2β-PE targeting affects cancer cells.
• To evaluate the efficacy of TRA2β-PE-targeting antisense oligonucleotides (ASOs) in preclinical cancer models.

Main Methods:

• Development and application of splice-switching antisense oligonucleotides (ASOs) targeting TRA2β-PE.
• Assessment of TRA2β protein levels and TRA2β-PE inclusion in cancer models.
• Analysis of transcriptomic alterations, signaling pathways (mTOR, p53), and anti-cancer phenotypes.
• Evaluation of ASO toxicity in 3D organoid and patient-derived xenograft models.

Main Results:

• TRA2β-PE-targeting ASOs successfully promote TRA2β-PE inclusion and decrease TRA2β protein levels.
• ASO treatment induces anti-cancer effects and significant transcriptomic changes, impacting RNA processing and key signaling pathways.
• TRA2β-PE-targeting ASOs exhibit toxicity in preclinical 3D organoid and in vivo xenograft models.
• The ASO's mechanism involves both reducing TRA2β protein and generating functional long non-coding RNAs from PE-containing transcripts.

Conclusions:

• TRA2β-PE functions as both a regulator of protein expression and a long non-coding RNA in cancer.
• Targeting oncogenic splicing factors via PE-targeting ASOs represents a novel and promising therapeutic strategy for cancer treatment.