MicroRNAs (miRNAs) are endogenous non-coding RNAs (ncRNAs) measuring ∼22 nucleotides in length; they were first discovered in 1993 (Lee et al., 1993; Bartel, 2004). Lee et al. (1993) reported that lin-4 negatively regulates the expression of lin-14 protein by binding to the 3′-untranslated region (3′UTR) of lin-14 messenger RNA (mRNA) in Caenorhabditis elegans. miRNAs are crucial post-transcriptional regulators of gene expression and known to pair with the 3′UTR of target mRNAs to either induce mRNA degradation or inhibit translation (Bartel, 2009). Moreover, these RNAs have been reported to be involved in the processes of various diseases, such as cancer (Iacona and Lutz, 2019; Iqbal et al., 2019), chronic pain (Lopez-Gonzalez et al., 2017; Tramullas et al., 2018), and cardiac diseases (Colpaert and Calore, 2019; Fitzsimons et al., 2020).

Circular RNAs (circRNAs) are endogenous ncRNAs with covalent closed-loop structures that were first discovered in viral RNA by Sanger et al. (1976). circRNAs possess high stability on account of their unique structure, which protects them from degradation by exonucleases (Jeck et al., 2013). This type of RNA has been confirmed to modulate gene expression by acting as miRNA sponges (Hansen et al., 2013a; Memczak et al., 2013) or RNA binding protein regulators (Li et al., 2015). Similar to miRNAs, circRNAs are involved in a number of human diseases, such as cancer (Wang et al., 2017; Patop and Kadener, 2018), neurodegenerative disorders (Floris et al., 2017; Huang et al., 2020), and cardiovascular diseases (Aufiero et al., 2019; Zhang et al., 2020).

Crosstalk of circRNAs and miRNAs refers to the communication and co-regulation between them. As two important gene-expression regulators, circRNAs interact with miRNAs and participate in regulating mRNA expression in various human diseases (Hansen et al., 2013a; Kristensen et al., 2019). Crosstalk between miRNAs and circRNAs has been extensively studied, but the relevant mechanisms remain incompletely understood. To date, two mechanisms have been identified: (1) circRNAs act as miRNA inhibitors/sponges. ciRS-7 (circular RNA sponge for miR-7), one of the most typical circRNAs, has been observed to show overlapping co-expression with miR-7 in mouse brain. ciRS-7 can sponge miR-7 to inhibit miR-7 activity extensively, thereby increasing the levels of miR-7 target genes (Hansen et al., 2013a). (2) miRNAs mediate circRNAs. ciRS-7, also known as CDR1as, has been confirmed to be cleaved by Argonaute 2 via miR-671 mediation in cultured cells (Hansen et al., 2011) and mouse brain (Kleaveland et al., 2018). Furthermore, ciRS-7 and its crosstalk with miRNAs have been found to exert a significant effect on sensorimotor gating and synaptic transmission (Piwecka et al., 2017).

Crosstalk between circRNAs and miRNAs may provide new avenues through which the mechanisms, diagnosis, and treatment of human diseases could be explored. Thus, in the present work, we provide a bibliographic analysis of the related literature to identify current global research trends and emerging topics in this field.

In this study, we performed a bibliographic analysis of studies on the crosstalk between miRNAs and circRNAs and found that research on this topic is well underway. circRNAs can communicate and co-regulate with miRNAs to regulate gene expression. Hansen and his colleagues published the first paper on the crosstalk between ciRS-7 and miR-671 in 2011 (Hansen et al., 2011). However, the number of publications on this subject exceed 10 per year until 2016. Thereafter, publications exceeded 100 papers per year in 2018 and reached 535 papers per year in 2020.

The mechanisms of crosstalk between miRNAs and circRNAs are incompletely understood. miRNAs and circRNAs have been proven to interact in the pathological process of many human diseases, including cancer, osteoarthritis (OA) and neuropathic pain (NP). circRNAs sponging miRNAs was a frequently mentioned mechanism of the crosstalk between circRNAs and miRNAs in human diseases. Zheng et al. (2016) revealed that circHIPK3, a circRNAs differently expresses between cancer and normal tissues, has 18 potential binding sites and can sponge 9 miRNAs to modulate human cell proliferation. Liu et al. (2016) reported that circRNA-CER competitively binds miR-136 to regulated MMP13 expression and participated in the degradation of chondrocyte extracellular matrix. Several circRNAs have been confirmed to regulate mRNA expression by sponge miRNAs, and then involved in neuroinflammation, neuronal autophagy, cell proliferation, and central sensitization in NP (Song et al., 2020). About the mechanisms of cancer, Hanse found miR-671 can directionally cleave ciRS-7 to release miR-7 that sponged by ciRS-7 (Hansen et al., 2013b). However, few studies researched the mechanism of miRNAs mediating circRNAs.

Neoplasms are the most common condition associated with research on the crosstalk between miRNAs and circRNAs; indeed, articles discussing neoplasms made up 74.04% of the total number of publications obtained, with a high h-index (56). Han and his colleagues revealed that circMTO1 inhibits the process of hepatocellular carcinoma by sponging miR-9 (Han et al., 2017). Zhang and his colleagues found that circFGFR1 upregulates the expression of CXCR4, the miR-381-3p target gene, to promote the progression of non-small cell lung cancer by miR-381-3p (Zhang et al., 2019b). The research findings of Zhang et al. (2017) were published in Molecular Cancer, which had the highest IF among the top 10 journals ranked by number of publications. Interactions between miRNAs and circRNAs have also been explored in other types of neoplasms, such as gastric cancer, breast cancer (Yang et al., 2019) and glioma (Xu et al., 2018). Most of the related research focuses on malignant tumors and the mechanism of circRNA as a miRNA sponge.

Biochemical and Biophysical Research Communications contributed the most to research on the crosstalk between miRNAs and circRNAs by publishing 64 articles with the highest h-index (33). However, in terms of IF, this journal placed ninth among the top 10 journals ranked by number of publications. Molecular Cancer, the IF of which was 15.302, was the only journal with an IF greater than 10 among the top 10 journals. Although the IF of the top 10 journals was not high, JIF Quartile shown that these journals ranked well in corresponding categories (33.33% of Q1 and 46.67% of Q2). These results suggest that the quality of most publications was reliable, but more high quality and ground-breaking researches are needed in this field. Furthermore, the crosstalk between circRNAs and miRNAs is a relatively new field, and it may be a possible reason for these results.

China is the major country contributing research on the crosstalk between miRNAs and circRNAs in human diseases. The country published 981 papers (96.84% of the total number of articles included in this work) and showed fairly high centrality (0.57). The United States ranked second in terms of countries with the greatest number of publications; the country published 42 papers and demonstrated the highest centrality (0.59) among the countries compared. Interestingly, China noticeably contributed more publications than the United States, but the centrality of the former was lower than that of the latter. This finding may be explained by the vast number of articles published by China alone, which could result in low centrality. The top 10 institutions ranked by number of publications were all Chinese universities, among which Nanjing Medical University ranked first, with 72 publications. Therefore, China is the leading country in research on the crosstalk between miRNAs and circRNAs in human diseases, and universities are the main institutional form in this field.

According to CiteSpace V, “glioblastoma,” “miR-7,” “skeletal muscle,” and “non-coding RNA” are the most popular keywords in the related research; these terms indicate potential research hotspots and frontiers. The four potential frontiers of research on the crosstalk between miRNAs and circRNAs in human diseases are as follows:

According to our analysis of keywords and references, research on the crosstalk between circRNAs and miRNAs mainly focuses on cancer, including glioma, gastric cancer, and ovarian cancer, and the related sponge mechanism. Journals in molecular, biology and genetics field were the main source of references for the published research. Most publications were published in journals dedicated to molecular, biology and immunology field.

To the best of our knowledge, this study is the first to use CiteSpace to perform a bibliographic analysis of publications on the crosstalk between miRNAs and circRNAs. However, this study presents some limitations. First, SCI-E of WoS, although an authoritative and comprehensive database in the medical field, was the only resource we selected for data acquisition; thus, some important findings published in other databases may have been missed. Second, the contributions and collaborations of authors were not analyzed because most of the authors were from China and different Chinese names could be translated to the same English name. Third, this study lacked an assessment of the overall quality of publications.

A total of 1,013 papers on the crosstalk between miRNAs and circRNAs in human diseases were published. The first paper was published in 2011 and initiated research in this field. The quality of most publications was relatively well in this field, but high-impact researches were needed. Biochemical and Biophysical Research Communications contributed the most to this field in terms of number of publications, and China produced the largest amount of research on this topic. In terms of institution, Nanjing Medical University published the largest number of related articles. At present, cancer is the most popular research area related to the crosstalk between miRNAs and circRNAs in human diseases. The latest burst keywords are “glioblastoma,” “miR-7,” “skeletal muscle,” and “non-coding RNA.” As far as we know, no bibliographic analysis has been conducted for publications on the crosstalk between circRNAs and miRNAs before. This study may provide researchers important clues on research trends and frontiers in this field.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Y-MC and X-QW: conceptualization and visualization. Y-MC: data curation, formal analysis, methodology, and writing – original draft. X-QW: funding acquisition and supervision. Y-MC, Y-LZ, XS, and X-QW: validation. Y-MC, Y-LZ, and XS: writing, review, and editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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