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A comprehensive pan-cancer analysis reveals cancer-associated robust isomiR expression landscapes in miRNA arm switching

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Abstract

MicroRNAs (miRNAs), important regulators of gene expression, play critical roles in various biological processes and tumorigenesis. To reveal the potential relationships between multiple isomiRs and arm switching, we performed a comprehensive pan-cancer analysis to discuss their roles in tumorigenesis and cancer prognosis. Our results showed that many miR-#-5p and miR-#-3p pairs from the two arms of pre-miRNA may have abundant expression levels, and they are often involved in distinct functional regulatory networks by targeting different mRNAs, although they may also interact with common targets. The two arms may show diverse isomiR expression landscapes, and their expression ratio might vary, mainly depending on tissue type. Dominantly expressed isomiRs can be used to determine distinct cancer subtypes that are associated with clinical outcome, indicating that they may be potential prognostic biomarkers. Our findings indicate robust and flexible isomiR expression landscapes that will enrich the study of miRNAs/isomiRs and aid in revealing the potential roles of multiple isomiRs yielded by arm switching in tumorigenesis.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

BLCA:

Bladder urothelial carcinoma

BRCA:

Breast invasive carcinoma

CHOL:

Cholangiocarcinoma

COAD:

Colon adenocarcinoma

ESCA:

Esophageal carcinoma

HNSC:

Head and neck squamous cell carcinoma

KICH:

Kidney chromophobe

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

LIHC:

Liver hepatocellular carcinoma

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

PRAD:

Prostate adenocarcinoma

STAD:

Stomach adenocarcinoma

THCA:

Thyroid carcinoma

UCEC:

Uterine corpus endometrial carcinoma

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 62171236 and 61771251), the key project of social development in Jiangsu Province (No. BE2022799), the key projects of Natural Science Research in Universities of Jiangsu Province (22KJA180006), the Qinglan Project in Jiangsu Province, the Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University (SKLB2022-K03), Sponsored by NUPTSF (No. NY220041), funding from Shandong Provincial Key Laboratory of Biophysics (2022KFKT001), and the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD).

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Authors and Affiliations

  1. Department of Bioinformatics, Smart Health Big Data Analysis and Location Services Engineering Lab of Jiangsu Province, School of Geographic and Biologic Information, Nanjing University of Posts and Telecommunications, Nanjing, 210023, China

    Li Guo, Dekang Ren, Yuting Zhang, Qiushi Wang & Shiyi Yu

  2. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing, 210023, China

    Xinru Xu, Lulu Luo & Tingming Liang

  3. Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou, 253023, China

    Jiafeng Yu

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  1. Li Guo
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  3. Yuting Zhang
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Contributions

Conceptualization, LG and TL; investigation, LG, DR, YZ, QW, SY, XX, JY, LL; writing—original draft preparation, LG and TL; writing—review and editing, LG and TL; supervision, TL; funding acquisition, LG and TL All authors have read and agreed to the published version of the manuscript.

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Correspondence to Tingming Liang.

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Communicated by Shuhua Xu.

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Supplementary Information

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438_2023_1997_MOESM1_ESM.tif

Supplementary file1 Distributions of target mRNAs of miR-#-5p and miR-#-3p. A. Pie distributions of targets in some miR-#-5p and miR-#-3p pairs (all of them are found with abundant interactions) indicate that few common targets are found, and most of targets are private. B. Examples of the shared enriched significant GO terms or KEGG pathways between randomly selected miRNA pairs (FDR < 0.05) (TIF 563 KB)

438_2023_1997_MOESM2_ESM.tif

Supplementary file2 Expression relationships of isomiRs from the two arms. A. Distribution of expression ratio of the two arms in cancers (based on the mean value). Each point indicates expression ratio of the two arms of miRNA (high expression/low expression), and the mean value is estimated. The total median value is highlighted (1.4886). B. Expression correlations of miRNA and target mRNA (obtained from starBase database). C. An example of the total expression distributions of miR-#-5p and miR-#-3p pairs across cancers based on the most dominant isomiR from the two arms. miR-21-5p and miR-21-3p show similar expression patterns across different tissues. D. A heatmap shows expression profiles of multiple isomiRs in tumor samples of BRCA. E. A heatmap shows expression profiles of multiple isomiRs in tumor samples of LUAD (TIF 1229 KB)

438_2023_1997_MOESM3_ESM.tif

Supplementary file3 Some isomiRs from the two arms may be associated with clinical outcome. A. IsomiRs generated from miR-21-5p and miR-21-3p show different expression patterns in diverse cancers, and some isomiR pairs are associated with the outcome of patients. * indicates |log2FC| > 1.5 and padj < 0.05. B. The expression distributions of some dominantly expressed isomiRs in 3 involved cancer types in Figure S3A. C. IsomiRs generated from miR-30a-5p and miR-30a-3p are associated with the outcome of patients, and dominantly isomiRs are significantly dysregulated in tumor samples. D. IsomiRs generated from miR-1307-5p and miR-1307-3p are associated with clinical outcome, and dominantly isomiRs are significantly dysregulated in tumor samples (TIF 1008 KB)

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Guo, L., Ren, D., Zhang, Y. et al. A comprehensive pan-cancer analysis reveals cancer-associated robust isomiR expression landscapes in miRNA arm switching. Mol Genet Genomics 298, 521–535 (2023). https://doi.org/10.1007/s00438-023-01997-4

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