Genome-wide Identification of A-to-I RNA Editing Events Provides the Functional Implications in PDAC

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Mar 10

PMID 36895481

Authors

Yue Mei

Dong Liang

Bin Ai

Tengjiao Wang

Shiwei Guo

Gang Jin

Dong Yu

Affiliations

Soon will be listed here.

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.

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References

Chan T, Lin C, Qi L, Fei J, Li Y, Yong K . A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut. 2013; 63(5):832-43. PMC: 3995272. DOI: 10.1136/gutjnl-2012-304037. View

Lucas A, Frado L, Hwang C, Kumar S, Khanna L, Levinson E . BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer. 2014; 120(13):1960-7. PMC: 5494829. DOI: 10.1002/cncr.28662. View

Gannon H, Zou T, Kiessling M, Gao G, Cai D, Choi P . Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun. 2018; 9(1):5450. PMC: 6303303. DOI: 10.1038/s41467-018-07824-4. View

Wang Z, Liu T, Xue W, Fang Y, Chen X, Xu L . ARNTL2 promotes pancreatic ductal adenocarcinoma progression through TGF/BETA pathway and is regulated by miR-26a-5p. Cell Death Dis. 2020; 11(8):692. PMC: 7443143. DOI: 10.1038/s41419-020-02839-6. View

Zhao H, Wang Q, Wang X, Zhu H, Zhang S, Wang W . Correlation Between RAB27B and p53 Expression and Overall Survival in Pancreatic Cancer. Pancreas. 2015; 45(2):204-10. PMC: 4714634. DOI: 10.1097/MPA.0000000000000453. View

Gu J, Huang W, Zhang J, Wang X, Tao T, Yang L . TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway. Front Oncol. 2021; 11:628353. PMC: 8012900. DOI: 10.3389/fonc.2021.628353. View

Yu Y, Zhou H, Kong Y, Pan B, Chen L, Wang H . The Landscape of A-to-I RNA Editome Is Shaped by Both Positive and Purifying Selection. PLoS Genet. 2016; 12(7):e1006191. PMC: 4965139. DOI: 10.1371/journal.pgen.1006191. View

Zhang F, Lu Y, Yan S, Xing Q, Tian W . SPRINT: an SNP-free toolkit for identifying RNA editing sites. Bioinformatics. 2017; 33(22):3538-3548. PMC: 5870768. DOI: 10.1093/bioinformatics/btx473. View

Nishikura K . Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010; 79:321-49. PMC: 2953425. DOI: 10.1146/annurev-biochem-060208-105251. View

10.

Zhang T, Wang Z, Liu Y, Huo Y, Liu H, Xu C . Plastin 1 drives metastasis of colorectal cancer through the IQGAP1/Rac1/ERK pathway. Cancer Sci. 2020; 111(8):2861-2871. PMC: 7419044. DOI: 10.1111/cas.14438. View

11.

Yalcin A, Clem B, Imbert-Fernandez Y, Ozcan S, Peker S, ONeal J . 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death Dis. 2014; 5:e1337. PMC: 4123086. DOI: 10.1038/cddis.2014.292. View

12.

Wang L, Zhi X, Zhu Y, Zhang Q, Wang W, Li Z . MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC. Oncotarget. 2015; 6(32):33805-22. PMC: 4741804. DOI: 10.18632/oncotarget.5668. View

13.

Min H, Lee Y, Zhao X, Park Y, Lee M, Lee J . TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion. Cell Signal. 2013; 26(2):398-408. DOI: 10.1016/j.cellsig.2013.08.002. View

14.

Zhou C, Wei Z, Zhang L, Yang Z, Liu Q . Systematically Characterizing A-to-I RNA Editing Neoantigens in Cancer. Front Oncol. 2020; 10:593989. PMC: 7758481. DOI: 10.3389/fonc.2020.593989. View

15.

Chigaev M, Yu H, Samuels D, Sheng Q, Oyebamiji O, Ness S . Genomic Positional Dissection of RNA Editomes in Tumor and Normal Samples. Front Genet. 2019; 10:211. PMC: 6435843. DOI: 10.3389/fgene.2019.00211. View

16.

Okugawa Y, Toiyama Y, Shigeyasu K, Yamamoto A, Shigemori T, Yin C . Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. J Transl Med. 2018; 16(1):366. PMC: 6299520. DOI: 10.1186/s12967-018-1740-z. View

17.

Bernal C, Silvano M, Tapponnier Y, Anand S, Angulo C, Ruiz i Altaba A . Functional Pro-metastatic Heterogeneity Revealed by Spiked-scRNAseq Is Shaped by Cancer Cell Interactions and Restricted by VSIG1. Cell Rep. 2020; 33(6):108372. DOI: 10.1016/j.celrep.2020.108372. View

18.

Lo Giudice C, Tangaro M, Pesole G, Picardi E . Investigating RNA editing in deep transcriptome datasets with REDItools and REDIportal. Nat Protoc. 2020; 15(3):1098-1131. DOI: 10.1038/s41596-019-0279-7. View

19.

Han L, Diao L, Yu S, Xu X, Li J, Zhang R . The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. Cancer Cell. 2015; 28(4):515-528. PMC: 4605878. DOI: 10.1016/j.ccell.2015.08.013. View

20.

Islam S, Kitagawa T, Baron B, Abiko Y, Chiba I, Kuramitsu Y . ITGA2, LAMB3, and LAMC2 may be the potential therapeutic targets in pancreatic ductal adenocarcinoma: an integrated bioinformatics analysis. Sci Rep. 2021; 11(1):10563. PMC: 8131351. DOI: 10.1038/s41598-021-90077-x. View