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Review
. 2022 Jun 24;23(13):7024.
doi: 10.3390/ijms23137024.

Critical Roles of Circular RNA in Tumor Metastasis via Acting as a Sponge of miRNA/isomiR

Li Guo  1 , Lin Jia  2 , Lulu Luo  2 , Xinru Xu  2 , Yangyang Xiang  1 , Yujie Ren  1 , Dekang Ren  1 , Lulu Shen  2 , Tingming Liang  2
Affiliations
Review

Critical Roles of Circular RNA in Tumor Metastasis via Acting as a Sponge of miRNA/isomiR

Li Guo et al. Int J Mol Sci. .

Abstract

Circular RNAs (circRNAs), a class of new endogenous non-coding RNAs (ncRNAs), are closely related to the carcinogenic process and play a critical role in tumor metastasis. CircRNAs can lay the foundation for tumor metastasis via promoting tumor angiogenesis, make tumor cells gain the ability of migration and invasion by regulating epithelial-mesenchymal transition (EMT), interact with immune cells, cytokines, chemokines, and other non-cellular components in the tumor microenvironment, damage the normal immune function or escape the immunosuppressive network, and further promote cell survival and metastasis. Herein, based on the characteristics and biological functions of circRNA, we elaborated on the effect of circRNA via circRNA-associated competing endogenous RNA (ceRNA) network by acting as miRNA/isomiR sponges on tumor angiogenesis, cancer cell migration and invasion, and interaction with the tumor microenvironment (TME), then explored the potential interactions across different RNAs, and finally discussed the potential clinical value and application as a promising biomarker. These results provide a theoretical basis for the further application of metastasis-related circRNAs in cancer treatment. In summary, we briefly summarize the diverse roles of a circRNA-associated ceRNA network in cancer metastasis and the potential clinical application, especially the interaction of circRNA and miRNA/isomiR, which may complicate the RNA regulatory network and which will contribute to a novel insight into circRNA in the future.

Keywords: cancer metastasis; circular RNA (circRNA); competing endogenous RNA (ceRNA) network; isomiR; microRNA (miRNA).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CircRNA biogenesis and multiple isomiRs in miRNA. (A): There are three types of circular RNAs: intronic circRNAs (ciRNA), exonic circRNAs with introns (EIciRNA), and exonic circRNA (ecircRNA). 1–3 indicates that alternative splicing of the same gene can produce three circRNAs; I-IV show that circRNA can regulate the expression of parent gene, acting as a miRNA sponge, interacting with RNA binding protein (RBP), and translating polypeptide, respectively; (B) CircRNA can bind to miRNA through miRNA response element (MRE), which further up-regulates the target gene regulated by miRNA. The dysregulation of target mRNAs may disturb relevant biological processes that can further contribute to cancer pathophysiology and developmental process; (C) Take hsa-mir-92a-1 as an example to demonstrate multiple isomiRs in miRNA locus due to alternative and imprecise cleavage of Drosha and Dicer, 3′ addition events, etc. The detailed expression data are derived from the colon adenocarcinoma cohort in TCGA (TCGA-COAD). The pre-miRNA stem-loop structure is presented, and the total expression distribution of multiple isomiRs in the miR-92a-3p locus is presented for all relevant isomiRs if reads per million mapped reads (RPM) >= 10. Ten dominantly expressed isomiR types are further screened if the isomiR type is detected in more than 40 individuals and has higher expression levels (the detailed locations on chromosomes are used to name the isomiR type). The highlighted red locations, 61–82 (chr13:91351361–91351382[+]), are the canonical miRNA sequence in the miRbase database [16,17]; (D) The detailed expression distributions for the ten isomiR types between normal and tumor samples. Except for 3 isomiR types, others show a significant expression difference in tumor samples than that in normal samples (significant down-regulated, padj < 0.05). Of these, the isomiRs of 61–83 and 61–84 are unexpectedly dominantly expressed, despite the fact that they are not canonical miRNA sequences. * indicates padj < 0.05 based on DESeq2 algorithm [18].
Figure 2
Figure 2
Examples of circRNA-associated ceRNA network based on expression patterns of circRNAs in cancers. (A) The RNA interactions based on down-regulated circRNA in specific cancer that may have a potential tumor suppressor role; (B) The RNA interactions based on up-regulated circRNA in specific cancer that may have a potential tumor oncogene role.
Figure 3
Figure 3
Widespread circRNA-associated ceRNAs and complex RNA interactions among different RNAs. (A) The distribution of scores of predicted candidate interactions between miRNAs and circRNAs is presented (data are obtained from Liu et al. [121]), and the median value of log2Score is 7.2761; the distribution of interaction number of miRNA, and the median interaction number is 6044; the distribution of interaction number of circRNA, and the median interaction number is 71. (B) An example of miRNA:circRNA interaction network shows the potential interactions between the two ncRNAs (all of them are detected with the higher scores). The real interaction number of miRNAs and circRNAs is also presented on the right. (C) An example of a potential circRNA-associated ceRNA network shows complex interactions among different RNAs in colorectal cancer. The dysregulated circRNAs are identified using GSE147597 data from the GEO database [124], and dysregulated relevant miRNAs/isomiRs (dominantly expressed) and some of their target mRNAs (dominantly expressed) are further obtained from TCGA-COAD. The miRNA:mRNA interactions are obtained from the starBase database [125,126], and all of these interactions are predicted by at least 3 algorithms. The detailed multiple isomiRs are presented in the network according to the detailed start and end positions on the chromosome. miR-32-5p:73-94 indicates the detailed location of hg38:chr9:109046273-109046294:− of isomiR in miR-32-5p locus; miR-16-5p:54-74 indicates hg38:chr3:160404754-160404774:+ (mir-16-2 precursor) of isomiR in miR-16-5p locus; miR-130a-3p:52-74 indicates hg38:chr11:57641252-57641274:+ of isomiR in miR-130a-3p locus; miR-140-3p:42-66 indicates hg38:chr16:69933142-69933166:+ of isomiR in miR-140-3p locus. These candidate interactions only present the biological relationships and dysregulated expression patterns as examples, and expression correlations are not estimated due to limited data; (D) The detailed expression distributions of isomiRs in miR-16-5p and miR-140-3p loci between tumor and normal samples. All of them are significantly up-regulated or down-regulated in tumor samples. * indicates log2FC > 1.5 and padj < 0.05 or log2FC < −1.5 and padj < 0.05; (E) According to involved target mRNAs in Figure 3C, primary functional analysis is performed, mainly including the potential contributions in hallmarks of cancer and KEGG pathways; (F) Functional enrichment analysis is performed using clusterProfiler [127].
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