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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Antisense gapmers selectively suppress individual oncogenic p73 splice isoforms and inhibit tumor growth in vivo
Stephan Emmrich1, Weiwei Wang, Katja John
1Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, D-18057 Rostock, Germany. emmrichs@med.uni-rostock.de
Background:
Differential mRNA splicing and alternative promoter usage of the TP73 gene results in the expression of multiple NH2-truncated isoforms that act as oncogenes. Abundant levels of these p73 variants in a variety of human cancers correlated with adverse clinical prognosis and response failure to conventional therapies, underscoring their relevance as marker for disease severity and target for cancer intervention. With respect to an equally important role for amino-truncated p73 splice forms (DeltaTAp73) and DeltaNp73 (summarized as DNp73) in the tumorigenic process, we designed locked nucleic acid (LNA) antisense oligonucleotide (ASO) gapmers against individual species that were complementary to DeltaEx2 and DeltaEx2/3 splice junctions and a region in exon 3B unique for DeltaN' and DeltaN.
Results:
Treatment of cancer cells with these ASOs resulted in a strong and specific reduction of tumorigenic p73 transcripts and proteins, importantly, without abolishing the wild-type p73 tumor suppressor form as observed with p73-shRNA. The specific antisense oligonucleotides rescued cells from apoptosis inhibition due to overexpression of their corresponding amino-truncated p73 isoform and decreased tumor cell proliferation. Furthermore, ASO-116 against DeltaEx2/3 coupled to magnetic nanobead polyethyleneimine (MNB/PEI) carriers significantly inhibited malignant melanoma growth, which correlated with a shift in the balance between endogenous TAp73 and DeltaEx2/3 towards apoptotic full-length p73.
Conclusion:
Our study demonstrates the successful development of LNA-ASOs that selectively differentiate between the closely related p73 oncoproteins, and provide new tools to further delineate their biological properties in different human malignancies and for therapeutic cancer targeting.
Insights
New locked nucleic acid antisense oligonucleotides (LNA-ASOs) selectively target oncogenic p73 variants, offering a promising strategy for cancer therapy without affecting tumor-suppressing p73. These LNA-ASOs reduce cancer cell proliferation and tumor growth.
Area of Science:
- Molecular biology
- Cancer research
- Oligonucleotide therapeutics
Background:
- TP73 gene mutations lead to oncogenic NH2-truncated p73 isoforms.
- High levels of p73 variants correlate with poor cancer prognosis and treatment failure.
- Amino-truncated p73 splice forms (DNp73) play a crucial role in tumorigenesis.
Purpose of the Study:
- To develop targeted therapies against oncogenic p73 isoforms.
- To create selective locked nucleic acid antisense oligonucleotide (LNA-ASO) gapmers against specific p73 variants.
- To investigate the therapeutic potential of LNA-ASOs in cancer treatment.
Main Methods:
- Design and synthesis of LNA-ASO gapmers targeting DeltaEx2, DeltaEx2/3 splice junctions, and exon 3B of TP73.
- Treatment of cancer cells with LNA-ASOs to assess p73 transcript and protein reduction.
- Evaluation of LNA-ASO effects on apoptosis, cell proliferation, and tumor growth in vivo.
- Coupling of ASO-116 with magnetic nanobead polyethyleneimine (MNB/PEI) carriers for melanoma treatment.
Main Results:
- LNA-ASOs specifically reduced oncogenic p73 transcripts and proteins without affecting wild-type p73.
- Antisense oligonucleotides rescued cells from apoptosis inhibition and decreased proliferation.
- ASO-116/MNB/PEI significantly inhibited melanoma growth, shifting the TAp73/DeltaEx2/3 balance towards full-length p73.
Conclusions:
- Successful development of LNA-ASOs for selective targeting of p73 oncoproteins.
- LNA-ASOs provide novel tools for studying p73 in human malignancies.
- Demonstrated therapeutic potential of LNA-ASOs for cancer intervention.
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