Genome-wide identification of A-to-I RNA editing events provides the functional implications in PDAC

Yue Mei; Dong Liang; Bin Ai; Tengjiao Wang; Shiwei Guo; Gang Jin; Dong Yu

doi:10.3389/fonc.2023.1092046

Genome-wide identification of A-to-I RNA editing events provides the functional implications in PDAC

Front Oncol. 2023 Feb 21:13:1092046. doi: 10.3389/fonc.2023.1092046. eCollection 2023.

Authors

Yue Mei^{1

2}, Dong Liang^{1

2}, Bin Ai^{1

2}, Tengjiao Wang^{1

2}, Shiwei Guo³, Gang Jin³, Dong Yu^{1

2}

Affiliations

¹ Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.
² Shanghai Key Laboratory of Cell Engineering, Shanghai, China.
³ Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.

Abstract

Introduction: RNA editing, a wide-acknowledged post-transcriptional mechanism, has been reported to be involved in the occurrence and development of cancer, especially the abnormal alteration of adenosine to inosine. However, fewer studies focus on pancreaticcancer. Therefore, we aimed to explore the possible linkages between altered RNA editing events and the development of PDAC.

Method: We characterized the global A-to-I RNA editing spectrum from RNA and matched whole-genome sequencing data of 41 primary PDAC and adjacent normal tissues. The following analyses were performed: different editing level and RNA expression analysis,pathway analysis, motif analysis, RNA secondary structure analysis, alternative splicing events analysis, and survival analysis.The RNA editing of single-cell RNA public sequencing data was also characterized.

Result: A large number of adaptive RNA editing events with significant differences in editing levels were identified, which are mainly regulated by ADAR1. Moreover, RNA editing in tumors has a higher editing level and more abundant editing sites in general. 140genes were screened out since they were identified with significantly different RNA editing events and were significantly different in expression level between tumor and matched normal samples. Further analysis showed a preference that in the tumor-specific group, they are mainly enriched in cancer-related signal pathways, while in the normal tissue-specific group, they are mainly enriched in pancreatic secretion. At the same time, we also found positively selected differentially edited sites in a series of cancer immune genes, including EGF, IGF1R, and PIK3CD. RNA editing might participate in pathogenisis of PDAC through regulating the alternative splicing and RNA secondary structure of important genesto further regulate gene expression and protein synthesis, including RAB27B and CERS4. Furthermore, single cell sequencing results showed that type2 ductal cells contributed the most to RNA editing events in tumors.

Conclusion: RNA editing is an epigenetic mechanism involved in the occurrence and development of pancreatic cancer, which has the potential to diagnose of PDAC and is closely related to the prognosis.

Keywords: PDAC; RNA editing; RNA secondary structure; alternative splicing; immune genes; prognosis.

Grants and funding

This work was sponsored by grants from the National Natural Science Funds of China (Grant No. 31801109), Shanghai Sailing Program (No. 20YF1458100), and school-level project (Project No. 2018QN02).