Related Experiment Video
Updated: Oct 25, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
An antisense circular RNA circSCRIB enhances cancer progression by suppressing parental gene splicing and translation
Jian Ma1, William W Du1, Kaixuan Zeng1
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
Abstract:
Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.
Insights
Antisense circular RNAs (circRNAs), like circSCRIB, are enriched in breast cancer. This study shows antisense circRNAs can promote cancer progression by affecting gene expression, offering potential therapeutic targets.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Circular RNAs (circRNAs) are non-coding RNAs found in mammalian cells.
- A subset of circRNAs are synthesized in an antisense orientation, with 209 identified as enriched in breast cancer.
- The tumor suppressor SCRIB gene produces antisense circRNAs, including circSCRIB (hsa_circ_0001831), which is highly enriched in breast cancer.
Purpose of the Study:
- To investigate the functional role of antisense circRNAs, specifically circSCRIB, in breast cancer.
- To determine if circSCRIB affects pre-mRNA splicing and mRNA translation of its parental SCRIB gene.
- To explore the impact of circSCRIB expression on cancer cell behavior and tumorigenesis.
Main Methods:
- Generation of a hsa_circ_0001831 expression construct to study its effects.
- Comparison with an exonic sequence construct to differentiate effects on splicing versus translation.
- Analysis of SCRIB mRNA production, protein translation, cell proliferation, migration, invasion, and tumorigenesis.
Main Results:
- Expression of circSCRIB led to decreased SCRIB mRNA production and increased cancer cell proliferation, migration, and invasion.
- An exonic sequence construct did not affect mRNA splicing but decreased protein translation, increasing E-cadherin and decreasing N-cadherin and vimentin.
- These changes resulted in enhanced cell migration, invasion, proliferation, colony formation, and tumorigenesis.
Conclusions:
- Antisense circRNAs, exemplified by circSCRIB, can modulate their parental transcripts.
- circSCRIB promotes breast cancer progression through mechanisms affecting mRNA splicing and translation.
- Antisense circRNAs represent a novel class of regulatory RNAs with potential as therapeutic targets in cancer.
Related Concept Videos
02:15Experimental RNAi
01:32RNA Splicing
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
01:22MicroRNAs
01:22MicroRNAs