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Updated: Jun 9, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
siRNAs Targeting Non-Human Species-Specific lncRNAs Trigger Cell Death in Human Colorectal Cancer Cells
Wan-Ying Feng1,2, Jun-Xiang Zeng1, Yan-Ru Chen3
1Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Species-specific long non-coding RNAs (lncRNAs) possess numerous unknown functions. We have recently reported that short interfering RNAs (siRNAs) designed to target mouse-specific lncRNAs caused cell death exclusively in human cancer cells, sparing normal human cells and mouse cancer cells. However, it is uncertain whether other non-human species-specific lncRNAs could also be applied as sequential targets for designing anti-tumor therapeutic siRNAs. In this research, we showed that siRNAs targeting rat or zebrafish-specific lncRNAs could exert similar cytotoxic effects against human colorectal cancer (CRC) cells while leaving normal human cells unaffected. Mechanistic investigations revealed that these siRNAs prompted apoptosis or pyroptosis in human CRC cells by triggering an IRF3-independent immune response against exogenous dsRNAs, based on the expression of protein gasdermin E (GSDME). Our study demonstrates that utilizing siRNAs to target non-human species-specific lncRNAs can trigger cell death in human CRC cells, indicating that non-human species-specific lncRNAs could serve as a promising reservoir for target libraries when designing anti-tumor siRNAs.
Insights
Targeting non-human species-specific long non-coding RNAs (lncRNAs) with small interfering RNAs (siRNAs) effectively kills human cancer cells. This approach spares normal human and non-human cells, offering a novel anti-tumor therapy strategy.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Long non-coding RNAs (lncRNAs) have largely unknown functions.
- Short interfering RNAs (siRNAs) targeting mouse-specific lncRNAs selectively induce cancer cell death.
Purpose of the Study:
- To investigate if non-human species-specific lncRNAs can be targeted by siRNAs for anti-tumor therapy.
- To explore the mechanisms of siRNA-induced cell death in human colorectal cancer (CRC) cells.
Main Methods:
- Designing siRNAs against rat and zebrafish-specific lncRNAs.
- Assessing the cytotoxic effects of these siRNAs on human CRC and normal human cells.
- Investigating the molecular mechanisms, including apoptosis, pyroptosis, and immune responses.
Main Results:
- siRNAs targeting rat or zebrafish lncRNAs induced cell death in human CRC cells.
- Normal human cells remained unaffected.
- Cell death occurred via apoptosis or pyroptosis, involving an IRF3-independent immune response and gasdermin E (GSDME) expression.
Conclusions:
- Non-human species-specific lncRNAs are viable targets for developing anti-tumor siRNAs.
- This strategy offers selective cancer cell killing with minimal impact on normal cells.
- Non-human lncRNAs represent a valuable resource for anti-cancer siRNA therapeutic development.
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02:39lncRNA - Long Non-coding RNAs
02:30siRNA - Small Interfering RNAs
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02:15Experimental RNAi
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