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A Nonsequencing Approach for the Rapid Detection of RNA Editing
Published on: April 21, 2022
ADAR-mediated RNA editing regulates PVR immune checkpoint in colorectal cancer
Cheng-Jia Qian1, Yu-Shan He2, Tao Guo2
1Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, China.
Abstract:
Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3'-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC.
Insights
ADAR-mediated RNA editing upregulates poliovirus receptor (PVR) expression in colorectal cancer (CRC). This discovery offers a potential new diagnostic biomarker for CRC, improving immunotherapy resistance understanding.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumor immunotherapy resistance is linked to ADAR-mediated RNA editing.
- Specific targets of this RNA editing in cancer remain largely unknown.
Purpose of the Study:
- Identify targets of ADAR-mediated RNA editing in colorectal cancer (CRC).
- Investigate the role of poliovirus receptor (PVR) in CRC progression and its regulation by RNA editing.
- Evaluate PVR RNA editing as a diagnostic biomarker for CRC.
Main Methods:
- Transcriptome sequencing analysis in two Chinese CRC cohorts.
- Experimental validation including gene expression analysis and cell-based assays (over-expression, knockdown).
- Luciferase reporter and actinomycin D assays to assess RNA stability and expression regulation.
Main Results:
- PVR and ADAR expression are significantly increased in CRC tumors.
- Upregulated PVR RNA editing was observed in CRC tumors, correlating positively with PVR and ADAR expression.
- ADAR manipulation altered PVR expression and RNA editing in CRC cells.
- RNA editing in the PVR 3'-UTR enhances PVR RNA expression, likely via increased RNA stability.
- A combined signature of PVR RNA editing and expression demonstrated promising diagnostic performance in CRC.
Conclusions:
- ADAR-mediated RNA editing plays a crucial role in upregulating PVR in CRC.
- PVR RNA editing represents a potential novel diagnostic biomarker for CRC.
- Findings provide new insights into RNA editing's contribution to tumor and immune functions in CRC.
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