Next Article in Journal
Inhibition of Oncogenic Src Ameliorates Silica-Induced Pulmonary Fibrosis via PI3K/AKT Pathway
Previous Article in Journal
G-Protein-Coupled Receptors Mediate Modulations of Cell Viability and Drug Sensitivity by Aberrantly Expressed Recoverin 3 within A549 Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 1
10.3390/ijms24010773
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Emerging Mutual Regulatory Roles between m6A Modification and microRNAs

by
Zongqin Mei
,
Yahao Mou
,
Nan Zhang
,
Xiaoyu Liu
,
Zuoshun He
* and
Shiyan Gu
*
Institute of Preventive Medicine, School of Public Health, Dali University, No. 22 Wanhua Road, Dali 671000, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(1), 773; https://doi.org/10.3390/ijms24010773
Submission received: 10 September 2022 / Revised: 29 October 2022 / Accepted: 4 November 2022 / Published: 1 January 2023
(This article belongs to the Topic MicroRNA: Mechanisms of Action, Physio-Pathological Implications, and Disease Biomarkers)
Browse Figures
Review Reports Versions Notes

Abstract

:
N6-metyladenosine (m6A), one of the most common RNA methylation modifications in mammals, has attracted extensive attentions owing to its regulatory roles in a variety of physiological and pathological processes. As a reversible epigenetic modification on RNAs, m6A is dynamically mediated by the functional interplay among the regulatory proteins of methyltransferases, demethylases and methyl-binding proteins. In recent years, it has become increasingly clear that m6A modification is associated with the production and function of microRNAs (miRNAs). In this review, we summarize the specific kinds of m6A modification methyltransferases, demethylases and methyl-binding proteins. In particular, we focus on describing the roles of m6A modification and its regulatory proteins in the production and function of miRNAs in a variety of pathological and physiological processes. More importantly, we further discuss the mediating mechanisms of miRNAs in m6A modification and its regulatory proteins during the occurrence and development of various diseases.

1. Introduction

N6-metyladenosine (m6A) modification refers to the methylation that occurs at the 6th nitrogen atom of adenine. Since firstly found in 1974, m6A has received extensive attention for regulating abundant internal modifications on various RNAs, including mRNAs, microRNAs (miRNAs), small nuclear RNAs (snRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) [1,2,3]. As we all know, the formation of m6A modification is dynamically catalyzed by methyltransferases and demethylases, also called “writers” and “erasers”, respectively. The binding proteins, named “readers”, can specifically combine with m6A modification and mediate m6A biological function in different pathological and physiological processes [4]. At present, m6A modification has been widely recognized as a reversible and dynamic epigenetic modification on various RNAs [5], and it is becoming increasingly clear that m6A potentially contributes to the occurrence and development of multiple diseases through altering RNA expressions or RNA functions [6]. Recently, the clinical value of m6A modification in diseases has become apparent, and m6A modification has been commonly utilized as a promising biomarker to diagnose, prevent and treat diseases [7].
As the most common non-coding RNAs, miRNAs exert their biological functions through interaction with RNAs or proteins [8]. Recently, emerging works of literature have demonstrated that miRNAs were modified by various chemical modifications, such as m6A, m1C, m5C and m7G, which affect the processing and functions of corresponding miRNAs [9,10,11]. Among these modifications, m6A attracted the most attention. As reported previous study, m6A modification is preferentially concentrated near the 3′-UTR, of which 67% contain ncRNAs, such as the binding sites of miRNAs, implicating that m6A and ncRNAs may jointly regulate target mRNAs through cooperation or competition [12]. The latest studies have found that m6A modification affects the cleavage, transport, stability and degradation of corresponding miRNAs and influences the interactions between miRNAs and long non-coding RNAs or proteins [13,14,15]. Interestingly, it is becoming increasingly clear that miRNAs also have critical roles in regulating m6A modification by changing the regulatory proteins of m6A modification [16]. Although some reviews summarize the interaction between m6A modification and miRNAs in cancer [17,18,19], studies on m6A modification and miRNAs are growing explosively, and their interactive effects are not limited to tumors. Thus, in this review, we summarize methyltransferases, demethylases and methyl-binding proteins which regulate m6A modification on RNAs. Subsequently, we sum up the essential roles of m6A modification on miRNAs in a variety of pathological and physiological processes. Lastly, we describe the mediation of miRNAs in m6A modification and discuss the interactive effects between m6A modification and miRNAs during the occurrence and development of the diseases.

2. Dynamic Regulation of m6A Modification

In recent years, more and more studies have found that m6A modification on RNAs can be dynamically regulated by dedicated methyltransferases, demethylases or methyl-binding proteins. A set of these regulatory proteins have been summarized in Figure 1.

2.1. “Writers”-m6A Methyltransferases

As shown in Figure 1, the addition of m6A modification to RNAs is executed by several components. Methyltransferase like 3 (METTL3), the first identified enzyme which catalyzes the m6A formation, was isolated and purified from Hela cells in 1994 [20]. In December 2013, Chuan’s group found methyltransferase like 14 (METTL14) has 43% homology with METTL3, and further exploring evidence demonstrated that METTL3 and METTL14 could form stable heterogeneous dimer to catalyze the formation of m6A modification [21]. In detail, METTL3 is the sole catalytic subunit, whereas METTL14 is essential for m6A deposition by stabilizing METTL3 conformation and recognizing substrate RNAs. The following studies showed that Wilms’ tumor-associated protein 1 (WTAP) was also an essential component for the formation of m6A [22]. Specifically, although WTAP has no methyltransferase activity, it acts as an adaptor protein to guide the METTL3-METTL14 heterodimers to co-locate on the nuclear speckle [23]. Interestingly, other adaptor proteins include vir like m6A methyltransferase associated (VIRMA, also named as KIAA1429) [24] and Cbl Proto-Oncogene Like 1(HAKAI, also known as CBLL1) [25], and zinc finger CCCH-type containing 13(ZC3H13/flacc) [26] can interact with WTAP and affect the level of m6A modification. In addition, lowering the expression of connexins such as RNA binding motif protein 15 (RBM15) and its para family like homologous protein RBM15B can also significantly reduce the level of m6A modification [27], suggesting that connexins are also an essential part of the formation of m6A modified methyltransferase 16(METTL16) [28]. Methyltransferases like 5(METTL5) [29] and zinc finger CCHC-type containing 4 (ZCCHC4) [30] have also been identified as m6A methyltransferases which individually catalyze m6A modification on specific structured RNAs (U6 snRNA, 28S rRNA, and 18S rRNA)

2.2. “Erasers”-m6A Demethylases

Demethylases, known as “erasers”, can selectively remove m6A marks from target RNAs and ensure that m6A methylation is a dynamic and reversible process. As far as we know, all the m6A demethylases currently identified belong to homologous proteins of Escherichia coli dioxygenase ALKB family: Fat mass and obesity associated protein (FTO) and AlkB family of nonheme Fe (II)/α-ketoglutarate (α-KG)-dependent dioxygenases 5 (ALKBH5) and ALKBH3 [31,32]. Initially, FTO was thought to be involved in the occurrence and development of obesity by regulating the expression of genes related to energy metabolism through demethylation [33]. In 2011, a study indicated that the bases which can be demethylated by FTO mainly contain m6A modification. Further exploration revealed that the m6A modification on mRNAs can be enhanced by siRNA-mediated knock-down of FTO expression while the upregulation of FTO protein inhibits m6A level [34]. This is the first confirmation that FTO can remove m6A methylation and the first report indicating that m6A modification is dynamic and reversible methylation. So far, FTO has been widely recognized as an m6A demethylase in a variety of RNAs from human or animal tissues [35]. As another “eraser” of m6A modification, ALKBH5 can oxidatively remove m6A modification on RNAs in vitro and in vivo [36]. Naturally, ALKBH5 is involved in the mRNA output, RNA metabolism and the assembly of mRNA processing factors in nuclear speckles [37]. It has been reported that depletion of ALKBH3 can effectively increase the m1A and m3C, suggesting that ALKBH3 is also a demethylase [38,39]. Interestingly, in addition to m1A and m3C modification, ALKBH3 can demethylate m6A modification in tRNA, and ALKBH3-interacted tRNA can increase protein efficiency [40]. At present, although FTO, ALKBH5 and ALKBH3 are homologous protetranslationins, they erase m6A marks on RNAs in an independent manner.

2.3. “Readers”-m6A Methyl-Binding Proteins

Similar to DNA methylation, the biological function of m6A modification on RNAs is performed by specific methylated proteins. Recent studies have indicated that m6A methyl-binding proteins are a class of protein family, which contains the YTH domain. As early as 2012, studies characterized YTH domain family protein 2 (YTHDF2), YTHDF3 and YTHDC1 as m6A binding proteins through the combination of RNA pull down and mass spectrometry [41]. Subsequently, the other YTH domain family protein members, YTHDF1 and YTHDC2, were also confirmed to bind with m6A modification [42,43]. More importantly, further functional studies showed that YTHDF1, YTHDF2 and YTHDF3 could mediate the degradation and translation while YTHDC1 and YTHDC2 were related to the splicing and nucleation of target mRNAs which were modified by m6A modification [44]. YTHDC1 has been reported to bind ncRNAs rather than mRNAs. [45]. In addition, Human heterogeneous nuclear ribonucleoprotein (HNRNP) A2/B1 can bind to miRNA through m6A modification and affect the splicing and transshipment of corresponding miRNA precursor, so as to regulate the miRNA generation and maturation [46]. Eukaryotic initiation factor 3 (EIF3) also has been identified as an m6A methylated binding protein of mRNA at 5′-UTR and involved in cap-independent translation [47]. ATP Binding Cassette Subfamily F Member 1 (ABCF1) has been evidenced as a critical mediator of m6A-promoted translation under stress and physiological conditions and further exploring indicated ABCF1-sensitive transcripts largely overlap with METTL3-dependent mRNA targets, supporting that ABCF1 may act as an m6A methyl-binding protein [48]. In 2018, it was shown that insulin-like growth factor 2 mRNA-binding proteins 1/2/3 (IGFBP1/2/3) were also methyl-binding proteins of m6A modification, which could increase the stability and translation efficiency of target mRNAs [49]. In addition to the proteins directly bound to the m6A modification mentioned above, some proteins can indirectly bind to m6A modification. As we all know, once the methylation modification occurs on RNAs, the conformation of RNA will be changed, and some binding sites will be uncovered, thus leading to the recognition by RNA binding proteins. This phenomenon is vividly known as ‘m6A switch’ [50]. For now, two types of m6A indirect binding proteins have been found, namely, HNRNPC (heterogeneous nuclear ribonucleoprotein C) and HNRNPG, which involve in transcription and maturation of mRNAs [51,52,53]. Furthermore, FMR1 (Fragile X Mental Retardation 1) is a sequence-context-dependent m6A reader, which can interact with m6A by depending on RNA secondary structure to inhibit its translation [54].

3. Mutual Regulatory Mechanisms between m6A Modification and miRNAs

Recently, a large number of studies have demonstrated that m6A modification on miRNAs play essential roles in various pathophysiological processes. Most interestingly, emerging evidence revealed that miRNAs also regulate m6A modification by altering expressions of m6A regulatory proteins [51,55]. So far, mutual regulatory mechanisms between m6A modification and miRNAs in multiple diseases have attracted a huge amount of attention.
As a series of noncoding and single-stranded small molecular RNA with a length of 18–24 nucleotides, miRNAs could target specific mRNA sites and promote degradation or inhibit translation of mRNA [56]. Although there are nearly 3000 miRNAs in mammals, the generation processes of different miRNAs are almost consistent. In detail, upon transcription from DNA, primary transcripts of miRNAs (pri-miRNAs) are spliced by RNase Ⅲ structure domain proteins and double-stranded RNA binding protein Drosha and Di George Syndrome critical region 8 (DGCR8) to form precursor of miRNAs (pre-miRNAs) in the nucleus. Then, pre-miRNAs are exported from nucleus into cytoplasm by forming a complex with a transporter protein exportin-5 and a GTP-binding nuclear protein Ran-GTP [53,54]. Once transported out of nucleus, pre-miRNAs are cleaved into mature miRNAs through another type III RNase Dicer. The mature miRNAs subsequently bind to mRNAs with the help of Ago proteins, thereby affecting the levels or translation processes of corresponding mRNAs [57]. Interestingly, advances in m6A modification in recent years have widely broadened mechanisms underlying miRNA processing and regulation. Specifically, emerging studies have shown that m6A modification and its regulatory proteins involve in the production of mature miRNAs, which in turn affect the level of m6A modification [58].

3.1. m6A Modifications Involves in miRNA Generation and Function

Current studies have indicated that m6A modification is involved in the generation process of miRNAs, thus affecting the level of mature miRNAs. Published results in the journal Nature in 2015 revealed that decreasing the level of m6A modification on pri-miRNAs by knocking down METTL3 expression could inhibit the binding of DGCR8 to pri-miRNAs, which led to about 70% miRNAs being downregulated by at least 30% [57]. Up to now, the mechanism according to which reduction of m6A modification on pri-miRNAs inhibits the maturation of miRNAs in a DGCR8-dependent manner has been found in different diseases. For example, catalyzed by over-expressed METTL3, high m6A modification can promote the maturity of miR-25 and miR-25-3p by strengthening the combination of DGCR8 and pri-miR-25 in pancreatic duct epithelial cells, and this may provoke malignant phenotype of pancreatic cancer cells [59]. The reduction level of m6A modification mediated by low expression of METTL3 and METTL14 makes the weaker recognition of pri-miR-126 by DGCR8, which hinders the maturation of miR-126, thereby activating the PI3K/AKT/mTOR pathway to promote the proliferation and activation of fibroblasts. Moreover, METTL3-dependent m6A was involved in the DGCR8-mediated maturation of pri-miR-126 in endometriosis development [60]. In addition, the interaction of METTL3 and DGCR8 positively modulates the biogenesis process of miR-873-5p, miR-365-3p and miR-221/222 in an m6A-dependent manner in different pathological processes, and as the simplest for specific miRNA, miR-873-5p participated in fighting colistin induced oxidative stress and apoptosis in kidney injury [61], miR-365-3p regulated chronic inflammatory pain induced by Complete Freund’s Adjuvant in the spinal cord [62], and miR-221/222 negatively mediate the PTEN expression, thus leading to the proliferation of bladder cancer cells [63]. In addition, cigarette smoke can stimulate the production of excess mature miRNA-93 in bronchial epithelial cells via enhanced m6A modification, which was mediated by overexpressed METTL3 [64]. METTL3 also plays a major catalytic role in m6A modification in unilateral ureteral obstruction mice and drove obstructive renal fibrosis development by promoting miR-21-5p maturation [65]. In addition, it has been indicated that silencing of METTL3 expression can elevate the levels of pri-miR-663 and m6A methylation-modified pri-miR-663, which resulted in suppressing of miR-663 maturation process in A549 and PC9LC cells [66]. In a manner similar to METTL3, the METTL14-mediated m6A marks also enhanced the recognition of pri-miR-126 by DGCR8, thus subsequently processing to mature miRNA-126, which is involved in hepatocellular carcinoma metastasis [60]. Different from the above mechanisms, METTL3 induced upregulation of miR-143-3p mostly depends on the shear effect of Dicer on pre-miR-143-3p in lung cancer cells [67]. Moreover, as in bone marrow-derived mesenchymal stem cells, METTL3 also methylate pre-miR-320, on which m6A modification is a key factor that is recognized and decayed by YTHDF2 [68]. METTL3 promoted the transition from pri-miR-1246 to mature miR-1246, of which upregulation can significantly enhance the metastasis ability of colorectal cancer cells [69]. METTL3-mediated m6A modification also promotes the expressions of 9 miRNAs, including miR-106b, miR-18a, miR-18b, miR-3607, miR-432, miR-30a, miR-320b, miR-320d and miR-320e, and bioinformatics analysis has shown that these miRNAs are involved in regulating signaling pathways closely related to malignant transformation induced by arsenite [70]. In addition, four miRNAs (miR-130a-3p, miR-130b-3p, miR-106b-5p and miR-301a-3p) are all related to short overall survival of kidney renal clear cell carcinoma patients and have significantly negative correlation with METTL14 mRNA [71]. Up to now, the importance of methyltransferases-catalyzed m6A modification on pri-miRNAs has been widely recognized, and a variety of methyltransferase components can affect the generation and function of miRNAs.
Besides methyltransferases, m6A demethylases and methyl-binding proteins are also involved in miRNA biogenesis. The earliest study showed that knocking down the FTO expression significantly increased levels of 42 miRNAs and decreased levels of 9 miRNAs [72]. A subsequent study reported that FTO regulates cell migration and invasion in breast cancer cells by inhibiting miR-181b-3p [73]. Moreover, FTO has been well evidenced to promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways [74]. ALKBH5 inhibits tumor growth and metastasis by inhibiting miR-107/LATS2 mediated YAP activity in non-small cell lung cancer [75]. Peng et al. indicated that ALKBH5, the most potent member related to patient outcomes and to suppressing esophageal cancer malignancy in cell and animal models, demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an m6A/DGCR8-dependent manner [76]. Interestingly, in human non-small cell lung cancer cells, the depletion of ALKBH5 did not change the miR-21-5p level but altered the m6A abundance on miR-21-5p, thereby changing the miR-21-5p silencing potency towards its target mRNAs, which finally impaired the proliferation and motility of human non-small cell lung cancer cells [77]. In addition, ALKBH5 demethylated pri-miR-320a-3p, thus blocking DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p in silica-inhaled mouse lung tissues [78].
In addition to being directly affected by m6A methyltransferases and demethylases, miRNA generation is also regulated by m6A methyl binding proteins. YTHDC1, a well-known m6A reader, facilitated the biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability. Furthermore, miR-30d represses pancreatic tumor genesis via suppressing aerobic glycolysis [79]. m6A reader protein HNRNPA2B1 also binds to a subset of m6A-modified pri-miRNA transcripts, thus interacting with DGCR8 and promoting primary miRNA processing, and depletion of HNRNPA2B1 caused a reduction in the levels of 61 miRNAs in HEK293 cells. Moreover, transiently overexpressed (5.4-fold) HNRNPA2B1 in MCF-7 cells led to significant alteration of more than 100 miRNAs, which regulate TGFβ and Notch signaling pathways according to MetaCore Enrichment analysis [80,81,82]. Yi et al. have reported that miR-185 transfer from vascular smooth muscle cells to endothelial cells is controlled by HNRNPA2B1 [83], but the role of m6A modification in this mediate process needs to be further explored. In addition, HNRNPA2B1 reads the m6A site on pri-miR-106b or pri-Let-7b to facilitate the maturing of miR-106b-5p or Let-7b in the lung cancer cells [84,85]. Another m6A binding protein, IGF2BP1, promotes serum response factor expression in an m6A-dependent manner by impairing the miRNA-directed downregulation of the serum response factor (SRF) mRNA in cancer cells [86]. In addition to regulating the generation process of miRNAs, m6A modification can directly modify mature miRNAs and affect their stability and degradation [72]. Of note, m6A modification on the E2F transcription factor 3 (E2F3) mRNA was required for the interaction between miR-660 and E2F3 mRNA in gastric cancer, indicating that m6A also affects the function of miRNA apart from participating in its production process [87].
In a word, emerging studies have identified the roles of m6A modification during the processing and maturation of miRNAs, which will surely provide good candidate targets for miRNA intervention. Although mechanisms underlying m6A modification affecting miRNA generation and function are diverse and complex, the general mechanisms are similar. We drew a schematic diagram, which take miR-30d [79], miR-21-5p [65] and pre-miR-25 [59] as examples, to show the specific mechanisms of m6A regulatory proteins regulating miRNAs (Figure 2). Additionally, the regulatory mechanisms of m6A modification and its regulatory proteins on miRNAs in different tissues or cells are summarized and shown in Table 1.

3.2. miRNAs Regulate the m6A Modification

Since miRNAs affect the protein level through interacting with mRNAs and m6A modification is a dynamic reversible methylation [88], it is rationality that miRNAs are involved in the regulation of m6A modification by affecting the regulatory proteins. At present, several studies have shown that miRNAs regulate m6A modification via sequence pairing of mRNAs of methyltransferases, demethylases, and methyl-binding proteins in various tissues [89]. In detail, METTL3 was identified as the direct target of miR-1269b [90] and miR-338-5p [91], thus inhibiting gastric cancer development. miR-33a is capable of reducing the METTL3 expression at both mRNA and protein levels, thus affecting proliferation, survival and invasion of non-small cell lung cancer [92]. Moreover, miR-600 can attenuate METTL3 expression and restrain the migration and proliferation of lung cancer cells [93]. Similarly, the down regulation of miR-524-5p also up-regulates the expression of METTL3 in non-small cell lung cancer cells [94]. miR-4429 targeted and repressed METTL3 to inhibit m6A-mediated stabilization of SEC62, a component belonging to tetrameric Sec62/Sec63-subcomplex of Sec-complex, thus hindering proliferation and encouraging apoptosis in gastric cancer cells [95]. Moreover, Cai et al. concluded that mammalian hepatitis B X-interacting protein (HBXIP) suppresses miRNA let-7g, thus up-regulating METTL3, which in turn promotes the expression of HBXIP through m6A modification, leading to stimulation or proliferation of breast cancer cells [96]. As an independent prognostic factor in hepatoblastoma patients, METTL3 was identified as a direct target of miR-186, of which low level led to high expression of METTL3, thus significantly inhibiting the proliferation, migration and invasion of hepatoblastoma cells [97]. Moreover, miR-320d has been evidenced to target METTL3, thus affecting KIF3C expression through changing m6A modification on KIF3C mRNA in prostate cancer cells [98]. Under the treatment of Mono-(2-ethylhexyl)phthalate (MEHP), miRNAs such as miR-16-1-3p, miR-101a-3p, miR-362-5p, miR-501-5p, miR-532-3p and miR-542-3p are dramatically activated in murine macrophage Raw 264.7 cells, and these miRNAs are all predicted to regulate METTL14, thus promoting m6A modification in Scavenger Receptor B type 1 (SR-B1) mRNA [99]. Cui et al. reported that miR-193a-3p directly targets ALKBH5 to inhibit the growth and promote the apoptosis of glioma cells by suppressing the AKT2 pathway both in vitro and in vivo [100]. Interestingly, circGPR137B acted as a sponge for miR-4739 to up-regulate its target FTO, which mediated m6A demethylation of circGPR137B and promoted its expression, thus finally forming a feedback loop comprising circGPR137B/miR-4739/FTO axis and affecting the hepatocellular carcinoma cells [101]. Results from Yang et al. indicated that imiR-155 directly targets FTO to negatively regulate its expression and increase m6A level in renal clear cell carcinoma cells. Regarding specific mechanisms, miR-155 is directly bound to the 3′-UTR of FTO mRNA and reduced FTO protein levels [102].
The methyl binding proteins of m6A modification are also directly targeted by miRNAs. In detail, Zheng et al. reported that miRNA-421-3p targets YTHDF1 to inhibit p65 mRNA translation, thus preventing inflammatory response in cerebral ischemia/reperfusion injury [103]. miR-376c also has been indicated to negatively modulate YTHDF1 expression in non-small cell lung cancer cells [104]. Negative correlations between the miR-145 level and YTHDF2 mRNA expression were observed in hepatocellular carcinoma [105] and epithelial ovarian cancer cells [106], and further detecting results showed that miR-145 decreased the luciferase activities of 3′-UTR of YTHDF2 mRNA, implicating that YTHDF2 is the direct target gene of miR-145 [105,106]. In addition, YTHDF2 mRNA is also regulated by miRNA-495 in prostate cancer cells [107] and miR-6125 in colorectal cancer cells [108]. Bioinformatics analysis from Hao et al. literature revealed IGF2BP1 as the putative target of miR-670, of which mimics and inhibitors were microinjected into parthenogenetic activation embryos, thus confirming these findings [109]. IGF2BP2, another m6A methyl binding protein, is highly expressed in thyroid cancer cells and identified as a target of miR-204 [110]. In addition, inhibition of miR-133b also resulted in the up regulation of IGF2BP2 in colorectal cancer cells [111]. Different from the above-mentioned mechanisms where miRNAs regulated m6A modification, results from Chen et al. indicated that overexpressing dicer increased the m6A modification level, and this was not achieved by alternating the quantity of m6A methyltransferases or demethylases in mouse embryonic fibroblasts. Further experiments showed that miRNAs regulate activity and location of METTL3, which subsequently modulate m6A modification and impede the reprogramming of mouse embryonic fibroblasts to pluripotent stem cells [112].
In a word, miRNAs can influence m6A modification by regulating the regulatory proteins of m6A and ultimately participate in a variety of pathological and physiological processes. We drew a schematic diagram, in which we take METTL3 [93], FTO [113] and YTHDF2 [108] as examples, to show the miRNAs involving in regulation of m6A modification and its biological effect (Figure 3). In addition, the effects of miRNAs on m6A regulatory proteins in different tissues or cells are summarized and shown in Table 2.
As mentioned above, m6A modification is regulated by different m6A regulatory proteins in a variety of diseases by promoting biosynthesis of miRNAs, and miRNA regulates the biological functions of m6A regulatory proteins. Based on this interplay, we summarized the change trends and regulation relationships of m6A regulatory proteins and miRNAs in tissues or cells during the occurrence and development of different diseases, as shown in Figure 4.

4. Conclusions and Prospect

M6A modification on miRNAs has been shown to control corresponding miRNA generation and functions, thereby regulating a variety of physiological and pathological events, including proliferation, metastasis, differentiation, apoptosis and homeostasis. Interestingly, miRNAs have the potential to regulate m6A modifications on different RNAs through methyltransferases, demethylases and methyl-binding proteins, thereby affecting gene expression or protein function. The interaction between m6A modification and miRNAs provides a new direction for exploring the potential regulatory mechanisms of gene expression in different diseases. More importantly, results of studies show that surrounding RNA modifications are increasing year by year due to crucial breakthroughs in NGS-based whole-transcriptome mapping methods [114,115]. Emerging published studies have revealed a dual role for m6A modification in driving chromatin dynamics and transcriptional outputs [49,116]. These latest and exciting findings will help to elucidate the biological relevance of m6A modifications of chromatin-associated RNAs in mammalian cells in the future [117]. Nevertheless, present understanding of mutual regulatory mechanisms between m6A modifications and miRNAs may be only the tip of the iceberg due to the diversity of miRNA types and regulatory proteins of m6A modification. The interplay mechanisms between m6A modification and miRNAs remain to be clarified. Notably, in the field of environment and health, only sporadic studies have indicated that m6A modification is involved in the toxic damage caused by environmental pollutants. Given the critical roles of m6A modification and miRNAs in disease, further study of m6A and miRNAs and their mutual regulating relationship in environment-related diseases will be worthy of further discussion.

Author Contributions

Z.M. and Y.M. contributed to writing the article, checking the content and sorting out the literature; N.Z. and X.L. contributed to reference collection, induction and verification. Z.H. and S.G. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grants from the National Natural Science Foundation of China (NO. 82060585) to Shiyan Gu.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors have no conflict of interest to declare that are relevant to the content of this article.

References

  1. Xu, J.; Wan, Z.; Tang, M.; Lin, Z.; Jiang, S.; Ji, L.; Gorshkov, K.; Mao, Q.; Xia, S.; Cen, D.; et al. N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling. Mol. Cancer 2020, 19, 163. [Google Scholar] [CrossRef] [PubMed]
  2. Desrosiers, R.; Friderici, K.; Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl. Acad. Sci. USA 1974, 71, 3971–3975. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Wang, S.; Lv, W.; Li, T.; Zhang, S.; Wang, H.; Li, X.; Wang, L.; Ma, D.; Zang, Y.; Shen, J.; et al. Dynamic regulation and functions of mRNA m6A modification. Cancer Cell Int. 2022, 22, 48. [Google Scholar] [CrossRef] [PubMed]
  4. Yang, Y.; Hsu, P.J.; Chen, Y.S.; Yang, Y.G. Dynamic transcriptomic m6A decoration: Writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018, 28, 616–624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Huang, H.; Weng, H.; Chen, J. The Biogenesis and Precise Control of RNA m6A Methylation. Trends Genet. 2020, 36, 44–52. [Google Scholar] [CrossRef]
  6. Sun, T.; Wu, R.; Ming, L. The role of m6A RNA methylation in cancer. Biomed. Pharmacother. 2019, 112, 108613. [Google Scholar] [CrossRef]
  7. Wei, W.; Ji, X.; Guo, X.; Ji, S. Regulatory Role of N6-methyladenosine (m6A) Methylation in RNA Processing and Human Diseases. J. Cell. Biochem. 2017, 118, 2534–2543. [Google Scholar] [CrossRef]
  8. Zepecki, J.P.; Karambizi, D.; Fajardo, J.E.; Snyder, K.M.; Guetta-Terrier, C.; Tang, O.Y.; Chen, J.S.; Sarkar, A.; Fiser, A.; Toms, S.A.; et al. miRNA-mediated loss of m6A increases nascent translation in glioblastoma. PLoS Genet. 2021, 17, e1009086. [Google Scholar] [CrossRef]
  9. Wiener, D.; Schwartz, S. The epitranscriptome beyond m6A. Nat. Rev. Genet. 2021, 22, 119–131. [Google Scholar] [CrossRef]
  10. Lin, C.; Ma, M.; Zhang, Y.; Li, L.; Long, F.; Xie, C.; Xiao, H.; Liu, T.; Tian, B.; Yang, K.; et al. Correction to: The N6-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway. Mol. Cancer 2022, 21, 80. [Google Scholar] [CrossRef]
  11. Khan, A.; Rehman, H.U.; Habib, U.; Ijaz, U. m6A-Finder: Detecting m6A methylation sites from RNA transcriptomes using physical and statistical properties based features. Comput. Biol. Chem. 2022, 97, 107640. [Google Scholar] [CrossRef] [PubMed]
  12. Meyer, K.D.; Saletore, Y.; Zumbo, P.; Elemento, O.; Mason, C.E.; Jaffrey, S.R. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012, 149, 1635–1646. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Zhang, B.; Chen, Z.; Tao, B.; Yi, C.; Lin, Z.; Li, Y.; Shao, W.; Lin, J.; Chen, J. m6A target microRNAs in serum for cancer detection. Mol. Cancer 2021, 20, 170. [Google Scholar] [CrossRef] [PubMed]
  14. Yi, Y.; Chen, X.; Zhang, J.; Zhu, J. Novel insights into the interplay between m6A modification and noncoding RNAs in cancer. Mol. Cancer 2020, 19, 121. [Google Scholar] [CrossRef]
  15. Tang, F.; Chen, L.; Gao, H.; Xiao, D.; Li, X. m6A: An Emerging Role in Programmed Cell Death. Front. Cell Dev. Biol. 2022, 10, 817112. [Google Scholar] [CrossRef]
  16. Sun, Z.; Wang, H.; Wang, Y.; Yuan, G.; Yu, X.; Jiang, H.; Wu, Q.; Yang, B.; Hu, Z.; Shi, F.; et al. MiR-103-3p targets the m6A methyltransferase METTL14 to inhibit osteoblastic bone formation. Aging Cell 2021, 20, e13298. [Google Scholar] [CrossRef]
  17. Yan, R.; Dai, W.; Wu, R.; Huang, H.; Shu, M. Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer. Cancer Lett. 2022, 534, 215615. [Google Scholar] [CrossRef]
  18. Han, B.; Chu, C.; Su, X.; Zhang, N.; Zhou, L.; Zhang, M.; Yang, S.; Shi, L.; Zhao, B.; Niu, Y.; et al. N6-methyladenosine-dependent primary microRNA-126 processing activated PI3K-AKT-mTOR pathway drove the development of pulmonary fibrosis induced by nanoscale carbon black particles in rats. Nanotoxicology 2020, 14, 1–20. [Google Scholar] [CrossRef]
  19. Chen, S.; Dong, J.; Luo, X.; Nie, Z.; Lu, S.; Liu, H.; Liu, J. Interaction between m6A and ncRNAs and Its Association with Diseases. Cytogenet. Genome Res. 2022, 162, 171–187. [Google Scholar] [CrossRef]
  20. Zeng, C.; Huang, W.; Li, Y.; Weng, H. Roles of METTL3 in cancer: Mechanisms and therapeutic targeting. J. Hematol. Oncol. 2020, 13, 117. [Google Scholar] [CrossRef]
  21. Liu, J.; Yue, Y.; Han, D.; Wang, X.; Fu, Y.; Zhang, L.; Jia, G.; Yu, M.; Lu, Z.; Deng, X.; et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 2014, 10, 93–95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Ping, X.L.; Sun, B.F.; Wang, L.; Xiao, W.; Yang, X.; Wang, W.J.; Adhikari, S.; Shi, Y.; Lv, Y.; Chen, Y.S.; et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014, 24, 177–189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Wang, T.; Kong, S.; Tao, M.; Ju, S. The potential role of RNA N6-methyladenosine in Cancer progression. Mol. Cancer 2020, 19, 88. [Google Scholar] [CrossRef]
  24. Zhu, W.; Wang, J.; Wei, J.; Lu, C. Role of m6A methyltransferase component VIRMA in multiple human cancers. Cancer Cell Int. 2021, 21, 172. [Google Scholar] [CrossRef]
  25. Wang, Y.; Zhang, L.; Ren, H.; Ma, L.; Guo, J.; Mao, D.; Lu, Z.; Lu, L.; Yan, D. Role of Hakai in m6A modification pathway in Drosophila. Nat. Commun. 2021, 12, 2159. [Google Scholar] [CrossRef]
  26. Wang, Q.; Xie, H.; Peng, H.; Yan, J.; Han, L.; Ye, G. ZC3H13 Inhibits the Progression of Hepatocellular Carcinoma through m6A-PKM2-Mediated Glycolysis and Enhances Chemosensitivity. J. Oncol. 2021, 2021, 1–15. [Google Scholar] [CrossRef]
  27. Zhang, Z.; Mei, Y.; Hou, M. Knockdown RBM15 Inhibits Colorectal Cancer Cell Proliferation and Metastasis Via N6-Methyladenosine (m6A) Modification of MyD88 mRNA. Cancer Biother Radiopharm 2021. [Google Scholar] [CrossRef]
  28. Mendel, M.; Chen, K.; Homolka, D.; Gos, P.; Pandey, R.R.; McCarthy, A.A.; Pillai, R.S. Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development. Mol. Cell 2018, 71, 986–1000. [Google Scholar] [CrossRef] [Green Version]
  29. van Tran, N.; Ernst, F.G.M.; Hawley, B.R.; Zorbas, C.; Ulryck, N.; Hackert, P.; Bohnsack, K.E.; Bohnsack, M.T.; Jaffrey, S.R.; Graille, M.; et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019, 47, 7719–7733. [Google Scholar] [CrossRef] [Green Version]
  30. Ma, H.; Wang, X.; Cai, J.; Dai, Q.; Natchiar, S.K.; Lv, R.; Chen, K.; Lu, Z.; Chen, H.; Shi, Y.G.; et al. N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat. Chem. Biol. 2019, 15, 88–94. [Google Scholar] [CrossRef]
  31. Kim, H.; Jang, S.; Lee, Y. The m6A(m)-independent role of FTO in regulating WNT signaling pathways. Life Sci. Alliance 2022, 5, e202101250. [Google Scholar] [CrossRef] [PubMed]
  32. Song, H.; Feng, X.; Zhang, H.; Luo, Y.; Huang, J.; Lin, M.; Jin, J.; Ding, X.; Wu, S.; Huang, H.; et al. METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy 2019, 15, 1419–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Mathiyalagan, P.; Adamiak, M.; Mayourian, J.; Sassi, Y.; Liang, Y.; Agarwal, N.; Jha, D.; Zhang, S.; Kohlbrenner, E.; Chepurko, E.; et al. FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation 2019, 139, 518–532. [Google Scholar] [CrossRef] [PubMed]
  34. Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Pan, T.; Yang, Y.; et al. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011, 7, 885–887. [Google Scholar] [CrossRef]
  35. Yang, Z.; Yu, G.; Zhu, X.; Peng, T.; Lv, Y. Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders. Genes Dis. 2022, 9, 51–61. [Google Scholar] [CrossRef] [PubMed]
  36. Yu, F.; Wei, J.; Cui, X.; Yu, C.; Ni, W.; Bungert, J.; Wu, L.; He, C.; Qian, Z. Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response. Nucleic Acids Res. 2021, 49, 5779–5797. [Google Scholar] [CrossRef]
  37. Shen, D.; Suo, F.; Song, Q.; Chang, J.; Zhang, T.; Hong, J.; Zheng, Y.; Liu, H. Development of formaldehyde dehydrogenase-coupled assay and antibody-based assays for ALKBH5 activity evaluation. J. Pharm. Biomed. Anal. 2019, 162, 9–15. [Google Scholar] [CrossRef]
  38. Zhao, Y.; Zhao, Q.; Kaboli, P.J.; Shen, J.; Li, M.; Wu, X.; Yin, J.; Zhang, H.; Wu, Y.; Lin, L.; et al. m1A Regulated Genes Modulate PI3K/AKT/mTOR and ErbB Pathways in Gastrointestinal Cancer. Transl. Oncol. 2019, 12, 1323–1333. [Google Scholar] [CrossRef]
  39. Chen, Z.; Qi, M.; Shen, B.; Luo, G.; Wu, Y.; Li, J.; Lu, Z.; Zheng, Z.; Dai, Q.; Wang, H. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 2019, 47, 2533–2545. [Google Scholar] [CrossRef] [Green Version]
  40. Wu, Y.; Zhan, S.; Xu, Y.; Gao, X. RNA modifications in cardiovascular diseases, the potential therapeutic targets. Life Sci. 2021, 278, 119565. [Google Scholar] [CrossRef]
  41. Dominissini, D.; Moshitch-Moshkovitz, S.; Schwartz, S.; Salmon-Divon, M.; Ungar, L.; Osenberg, S.; Cesarkas, K.; Jacob-Hirsch, J.; Amariglio, N.; Kupiec, M.; et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 2012, 485, 201–206. [Google Scholar] [CrossRef] [PubMed]
  42. Liu, R.; Kasowitz, S.D.; Homolka, D.; Leu, N.A.; Shaked, J.T.; Ruthel, G.; Jain, D.; Lin, H.; Keeney, S.; Luo, M.; et al. YTHDC2 is essential for pachytene progression and prevents aberrant microtubule-driven telomere clustering in male meiosis. Cell Rep. 2021, 37, 110110. [Google Scholar] [CrossRef] [PubMed]
  43. Kan, L.; Ott, S.; Joseph, B.; Park, E.S.; Dai, W.; Kleiner, R.E.; Claridge-Chang, A.; Lai, E.C. A neural m6A/Ythdf pathway is required for learning and memory in Drosophila. Nat. Commun. 2021, 12, 1458. [Google Scholar] [CrossRef] [PubMed]
  44. Li, L.; Xie, R.; Wei, Q. Network analysis of miRNA targeting m6A-related genes in patients with esophageal cancer. PeerJ 2021, 9, e11893. [Google Scholar] [CrossRef]
  45. Widagdo, J.; Anggono, V.; Wong, J.J. The multifaceted effects of YTHDC1-mediated nuclear m6A recognition. Trends Genet. 2022, 38, 325–332. [Google Scholar] [CrossRef] [PubMed]
  46. Liu, Y.; Shi, S.L. The roles of hnRNP A2/B1inRNA biology and disease. WIREs RNA 2021, 12, e1612. [Google Scholar] [CrossRef]
  47. Gomes-Duarte, A.; Lacerda, R.; Menezes, J.; Romão, L. eIF3: A factor for human health and disease. RNA Biol. 2018, 15, 26–34. [Google Scholar] [CrossRef] [Green Version]
  48. Coots, R.A.; Liu, X.; Mao, Y.; Dong, L.; Zhou, J.; Wan, J.; Zhang, X.; Qian, S. m6A Facilitates eIF4F-Independent mRNA Translation. Mol. Cell 2017, 68, 504–514. [Google Scholar] [CrossRef]
  49. Huang, H.; Weng, H.; Sun, W.; Qin, X.; Shi, H.; Wu, H.; Zhao, B.S.; Mesquita, A.; Liu, C.; Yuan, C.L.; et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 2018, 20, 285–295. [Google Scholar] [CrossRef]
  50. Sun, L.; Wan, A.; Zhou, Z.; Chen, D.; Liang, H.; Liu, C.; Yan, S.; Niu, Y.; Lin, Z.; Zhan, S.; et al. RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer. Gut 2021, 70, 1698–1712. [Google Scholar] [CrossRef]
  51. Zhou, K.I.; Parisien, M.; Dai, Q.; Liu, N.; Diatchenko, L.; Sachleben, J.R.; Pan, T. N6-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding. J. Mol. Biol. 2016, 428, 822–833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Liu, N.; Dai, Q.; Zheng, G.; He, C.; Parisien, M.; Pan, T. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 2015, 518, 560–564. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Liu, N.; Zhou, K.I.; Parisien, M.; Dai, Q.; Diatchenko, L.; Pan, T. N 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017, 45, 6051–6063. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Edupuganti, R.R.; Geiger, S.; Lindeboom, R.G.H.; Shi, H.; Hsu, P.J.; Lu, Z.; Wang, S.; Baltissen, M.P.A.; Jansen, P.W.T.C.; Rossa, M.; et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat. Struct. Mol. Biol. 2017, 24, 870–878. [Google Scholar] [CrossRef]
  55. Dai, D.; Wang, H.; Zhu, L.; Jin, H.; Wang, X. N6-methyladenosine links RNA metabolism to cancer progression. Cell Death Dis. 2018, 9, 113–124. [Google Scholar] [CrossRef] [Green Version]
  56. Afonso-Grunz, F.; Müller, S. Principles of miRNA–mRNA interactions: Beyond sequence complementarity. Cell. Mol. Life Sci. 2015, 72, 3127–3141. [Google Scholar] [CrossRef]
  57. Alarcón, C.R.; Lee, H.; Goodarzi, H.; Halberg, N.; Tavazoie, S.F. N6-methyladenosine marks primary microRNAs for processing. Nature 2015, 519, 482–485. [Google Scholar] [CrossRef] [Green Version]
  58. Saliminejad, K.; Khorram Khorshid, H.R.; Soleymani Fard, S.; Ghaffari, S.H. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J. Cell. Physiol. 2019, 234, 5451–5465. [Google Scholar] [CrossRef]
  59. Zhang, J.; Bai, R.; Li, M.; Ye, H.; Wu, C.; Wang, C.; Li, S.; Tan, L.; Mai, D.; Li, G.; et al. Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat. Commun. 2019, 10, 1858. [Google Scholar] [CrossRef] [Green Version]
  60. Zailaie, S.A.; Sergi, C.M. MiR-126 in Hepatocellular Carcinoma and Cholangiocellular Carcinoma: A Reappraisal with an in situ Detection of miR-126. Ann. Clin. Lab. Sci. 2022, 52, 73–85. [Google Scholar]
  61. Wang, J.; Ishfaq, M.; Xu, L.; Xia, C.; Chen, C.; Li, J. METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway. Front. Pharmacol. 2019, 10, 517. [Google Scholar] [CrossRef] [PubMed]
  62. Zhang, C.; Wang, Y.; Peng, Y.; Xu, H.; Zhou, X. METTL3 regulates inflammatory pain by modulating m6A-dependent pri-miR-365-3p processing. FASEB J. 2020, 34, 122–132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Han, J.; Wang, J.; Yang, X.; Yu, H.; Zhou, R.; Lu, H.; Yuan, W.; Lu, J.; Zhou, Z.; Lu, Q.; et al. METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol. Cancer 2019, 18, 110. [Google Scholar] [CrossRef] [Green Version]
  64. Wang, Z.; Sun, W.; Li, R.; Liu, Y. miRNA-93-5p in exosomes derived from M2 macrophages improves lipopolysaccharide-induced podocyte apoptosis by targeting Toll-like receptor 4. Bioengineered 2022, 13, 7683–7696. [Google Scholar] [CrossRef] [PubMed]
  65. Liu, E.; Lv, L.; Zhan, Y.; Ma, Y.; Feng, J.; He, Y.; Wen, Y.; Zhang, Y.; Pu, Q.; Ji, F.; et al. METTL3/N6-methyladenosine/ miR-21-5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF-κB pathway activation. J. Cell. Mol. Med. 2021, 25, 7660–7674. [Google Scholar] [CrossRef]
  66. Li, S.; Lu, X.; Zheng, D.; Chen, W.; Li, Y.; Li, F. Methyltransferase-like 3 facilitates lung cancer progression by accelerating m6A methylation-mediated primary miR-663 processing and impeding SOCS6 expression. J. Cancer Res. Clin. Oncol. 2022, 148, 3485–3499. [Google Scholar] [CrossRef]
  67. Wang, H.; Deng, Q.; Lv, Z.; Ling, Y.; Hou, X.; Chen, Z.; Dinglin, X.; Ma, S.; Li, D.; Wu, Y.; et al. N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1. Mol. Cancer 2019, 18, 181. [Google Scholar] [CrossRef] [Green Version]
  68. Yan, G.; Yuan, Y.; He, M.; Gong, R.; Lei, H.; Zhou, H.; Wang, W.; Du, W.; Ma, T.; Liu, S.; et al. m6A Methylation of Precursor-miR-320/RUNX2 Controls Osteogenic Potential of Bone Marrow-Derived Mesenchymal Stem Cells. Mol. Ther. Nucleic Acids 2020, 19, 421–436. [Google Scholar] [CrossRef]
  69. Peng, W.; Li, J.; Chen, R.; Gu, Q.; Yang, P.; Qian, W.; Ji, D.; Wang, Q.; Zhang, Z.; Tang, J.; et al. Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway. J. Exp. Clin. Cancer Res. 2019, 38, 393. [Google Scholar] [CrossRef] [Green Version]
  70. Gu, S.; Sun, D.; Dai, H.; Zhang, Z. N6-methyladenosine mediates the cellular proliferation and apoptosis via microRNAs in arsenite-transformed cells. Toxicol. Lett. 2018, 292, 1–11. [Google Scholar] [CrossRef]
  71. Wang, Q.; Zhang, H.; Chen, Q.; Wan, Z.; Gao, X.; Qian, W. Identification of METTL14 in Kidney Renal Clear Cell Carcinoma Using Bioinformatics Analysis. Dis. Markers 2019, 2019, 5648783. [Google Scholar] [CrossRef] [PubMed]
  72. Berulava, T.; Rahmann, S.; Rademacher, K.; Klein-Hitpass, L.; Horsthemke, B. N6-Adenosine Methylation in MiRNAs. PLoS ONE 2015, 10, e118438. [Google Scholar] [CrossRef] [PubMed]
  73. Xu, Y.; Ye, S.; Zhang, N.; Zheng, S.; Liu, H.; Zhou, K.; Wang, L.; Cao, Y.; Sun, P.; Wang, T. The FTO/miR-181b-3p/ARL5B signaling pathway regulates cell migration and invasion in breast cancer. Cancer Commun. 2020, 40, 484–500. [Google Scholar] [CrossRef] [PubMed]
  74. Zhou, G.; Yan, K.; Liu, J.; Gao, L.; Jiang, X.; Fan, Y. FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner. Cell Death Discov. 2021, 7, 329. [Google Scholar] [CrossRef]
  75. Jin, D.; Guo, J.; Wu, Y.; Yang, L.; Wang, X.; Du, J.; Dai, J.; Chen, W.; Gong, K.; Miao, S.; et al. m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC. Mol. Cancer 2020, 19, 40. [Google Scholar] [CrossRef] [Green Version]
  76. Chen, P.; Li, S.; Zhang, K.; Zhao, R.; Cui, J.; Zhou, W.; Liu, Y.; Zhang, L.; Cheng, Y. N6-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression. Oncogene 2021, 40, 5600–5612. [Google Scholar] [CrossRef]
  77. Wang, H.; Song, X.; Song, C.; Wang, X.; Cao, H. m6A-seq analysis of microRNAs reveals that the N6-methyladenosine modification of miR-21–5p affects its target expression. Arch. Biochem. Biophys. 2021, 711, 109023. [Google Scholar] [CrossRef]
  78. Sun, W.; Li, Y.; Ma, D.; Liu, Y.; Xu, Q.; Cheng, D.; Li, G.; Ni, C. ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1. Cell Mol. Biol. Lett. 2022, 27, 26. [Google Scholar] [CrossRef]
  79. Hou, Y.; Zhang, Q.; Pang, W.; Hou, L.; Liang, Y.; Han, X.; Luo, X.; Wang, P.; Zhang, X.; Li, L.; et al. YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect. Cell Death Differ. 2021, 28, 3105–3124. [Google Scholar] [CrossRef]
  80. Jiang, L.; Lin, W.; Zhang, C.; Ash, P.E.A.; Verma, M.; Kwan, J.; van Vliet, E.; Yang, Z.; Cruz, A.L.; Boudeau, S.; et al. Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy. Mol. Cell 2021, 81, 4209–4227. [Google Scholar] [CrossRef]
  81. Klinge, C.M.; Piell, K.M.; Tooley, C.S.; Rouchka, E.C. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Sci. Rep. 2019, 9, 9430. [Google Scholar] [CrossRef] [PubMed]
  82. Luo, K. Signaling Cross Talk between TGF-beta/Smad and Other Signaling Pathways. Cold Spring Harb. Perspect. Biol. 2017, 9, a022137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Si, Y.; Liu, F.; Wang, D.; Fang, C.; Tang, X.; Guo, B.; Shi, Z.; Dong, Z.; Guo, D.; Yue, J.; et al. Exosomal Transfer of miR-185 Is Controlled by hnRNPA2B1 and Impairs Re-endothelialization After Vascular Injury. Front. Cell Dev. Biol. 2021, 9, 619444. [Google Scholar] [CrossRef] [PubMed]
  84. Rong, L.; Xu, Y.; Zhang, K.; Jin, L.; Liu, X. HNRNPA2B1 inhibited SFRP2 and activated Wnt-beta/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathol. Res. Pract. 2022, 233, 153794. [Google Scholar] [CrossRef]
  85. Li, K.; Gao, S.; Ma, L.; Sun, Y.; Peng, Z.; Wu, J.; Du, N.; Ren, H.; Tang, S.; Sun, X. Stimulation of Let-7 Maturation by Metformin Improved the Response to Tyrosine Kinase Inhibitor Therapy in an m6A Dependent Manner. Front. Oncol. 2022, 11, 731561. [Google Scholar] [CrossRef]
  86. Müller, S.; Glaß, M.; Singh, A.K.; Haase, J.; Bley, N.; Fuchs, T.; Lederer, M.; Dahl, A.; Huang, H.; Chen, J.; et al. IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res. 2019, 47, 375–390. [Google Scholar] [CrossRef] [Green Version]
  87. He, X.; Shu, Y. RNA N6-methyladenosine modification participates in miR-660/E2F3 axis-mediated inhibition of cell proliferation in gastric cancer. Pathol.-Res. Pract. 2019, 215, 152393. [Google Scholar] [CrossRef]
  88. Chen, Y.; Lin, Y.; Shu, Y.; He, J.; Gao, W. Interaction between N6-methyladenosine (m6A) modification and noncoding RNAs in cancer. Mol. Cancer 2020, 19, 84. [Google Scholar] [CrossRef]
  89. Ma, J.Z.; Yang, F.; Zhou, C.C.; Liu, F.; Yuan, J.H.; Wang, F.; Wang, T.T.; Xu, Q.G.; Zhou, W.P.; Sun, S.H. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6 -methyladenosine-dependent primary MicroRNA processing. Hepatology 2017, 65, 529–543. [Google Scholar] [CrossRef]
  90. Kang, J.; Huang, X.; Dong, W.; Zhu, X.; Li, M.; Cui, N. MicroRNA-1269b inhibits gastric cancer development through regulating methyltransferase-like 3 (METTL3). Bioengineered 2021, 12, 1150–1160. [Google Scholar] [CrossRef]
  91. Wang, G.; Zhang, Z.; Xia, C. Long non-coding RNA LINC00240 promotes gastric cancer progression via modulating miR-338-5p/METTL3 axis. Bioengineered 2021, 12, 9678–9691. [Google Scholar] [CrossRef] [PubMed]
  92. Du, M.; Zhang, Y.; Mao, Y.; Mou, J.; Zhao, J.; Xue, Q.; Wang, D.; Huang, J.; Gao, S.; Gao, Y. MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA. Biochem. Biophys. Res. Commun. 2017, 482, 582–589. [Google Scholar] [CrossRef] [PubMed]
  93. Wei, W.; Huo, B.; Shi, X. miR-600 inhibits lung cancer via downregulating the expression of METTL3. Cancer Manag. Res. 2019, 11, 1177–1187. [Google Scholar] [CrossRef] [Green Version]
  94. Xie, H.; Yao, J.; Wang, Y.; Ni, B. Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis. Drug Deliv. 2022, 29, 1257–1271. [Google Scholar] [CrossRef]
  95. He, H.; Wu, W.; Sun, Z.; Chai, L. MiR-4429 prevented gastric cancer progression through targeting METTL3 to inhibit m6A-caused stabilization of SEC62. Biochem. Biophys. Res. Commun. 2019, 517, 581–587. [Google Scholar] [CrossRef]
  96. Cai, X.; Wang, X.; Cao, C.; Gao, Y.; Zhang, S.; Yang, Z.; Liu, Y.; Zhang, X.; Zhang, W.; Ye, L. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018, 415, 11–19. [Google Scholar] [CrossRef]
  97. Cui, X.; Wang, Z.; Li, J.; Zhu, J.; Ren, Z.; Zhang, D.; Zhao, W.; Fan, Y.; Zhang, D.; Sun, R. Cross talk between RNA N6-methyladenosine methyltransferase-like 3 and miR-186 regulates hepatoblastoma progression through Wnt/β-catenin signalling pathway. Cell Prolif. 2020, 53, e12768. [Google Scholar] [CrossRef] [Green Version]
  98. Ma, H.; Zhang, F.; Zhong, Q.; Hou, J. METTL3-mediated m6A modification of KIF3C-mRNA promotes prostate cancer progression and is negatively regulated by miR-320d. Aging 2021, 13, 22332–22344. [Google Scholar] [CrossRef]
  99. Park, M.H.; Jeong, E.; Choudhury, M. Mono-(2-Ethylhexyl)phthalate Regulates Cholesterol Efflux via MicroRNAs Regulated m6A RNA Methylation. Chem. Res. Toxicol. 2020, 33, 461–469. [Google Scholar] [CrossRef]
  100. Cui, Y.; Wang, Q.; Lin, J.; Zhang, L.; Zhang, C.; Chen, H.; Qian, J.; Luo, C. miRNA-193a-3p Regulates the AKT2 Pathway to Inhibit the Growth and Promote the Apoptosis of Glioma Cells by Targeting ALKBH5. Front. Oncol. 2021, 11, 600451. [Google Scholar] [CrossRef]
  101. Liu, L.; Gu, M.; Ma, J.; Wang, Y.; Li, M.; Wang, H.; Yin, X.; Li, X. CircGPR137B/miR-4739/FTO feedback loop suppresses tumorigenesis and metastasis of hepatocellular carcinoma. Mol. Cancer 2022, 21, 149. [Google Scholar] [CrossRef] [PubMed]
  102. Yang, W.; Xie, L.; Wang, P.; Zhuang, C. MiR-155 regulates m6A level and cell progression by targeting FTO in clear cell renal cell carcinoma. Cell. Signal. 2022, 91, 110217. [Google Scholar] [CrossRef] [PubMed]
  103. Zheng, L.; Tang, X.; Lu, M.; Sun, S.; Xie, S.; Cai, J.; Zan, J. microRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting m6A Reader YTHDF1 to inhibit p65 mRNA translation. Int. Immunopharmacol. 2020, 88, 106937. [Google Scholar] [CrossRef]
  104. Zhou, J.; Xiao, D.; Qiu, T.; Li, J.; Liu, Z. Loading MicroRNA-376c in Extracellular Vesicles Inhibits Properties of Non-Small Cell Lung Cancer Cells by Targeting YTHDF1. Technol. Cancer Res. Treat. 2020, 19, 1180565672. [Google Scholar] [CrossRef]
  105. Yang, Z.; Li, J.; Feng, G.; Gao, S.; Wang, Y.; Zhang, S.; Liu, Y.; Ye, L.; Li, Y.; Zhang, X. MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein. J. Biol. Chem. 2017, 292, 3614–3623. [Google Scholar] [CrossRef] [Green Version]
  106. Li, J.; Wu, L.; Pei, M.; Zhang, Y. YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. J. Ovarian Res. 2020, 13, 111. [Google Scholar] [CrossRef]
  107. Du, C.; Lv, C.; Feng, Y.; Yu, S. Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. J. Exp. Clin. Cancer Res. 2020, 39, 223. [Google Scholar] [CrossRef]
  108. Li, H.; Zhang, N.; Jiao, X.; Wang, C.; Sun, W.; He, Y.; Ren, G.; Huang, S.; Li, M.; Chang, Y.; et al. Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3β. Clin. Transl. Med. 2021, 11, e602. [Google Scholar] [CrossRef]
  109. Hao, J.; Hu, H.; Jiang, Z.; Yu, X.; Li, C.; Chen, L.; Xia, Y.; Liu, D.; Wang, D. microRNA-670 modulates Igf2bp1 expression to regulate RNA methylation in parthenogenetic mouse embryonic development. Sci. Rep. 2020, 10, 4782. [Google Scholar] [CrossRef] [Green Version]
  110. Ye, M.; Dong, S.; Hou, H.; Zhang, T.; Shen, M. Oncogenic Role of Long Noncoding RNAMALAT1 in Thyroid Cancer Progression through Regulation of the miR-204/IGF2BP2/m6A-MYC Signaling. Mol. Ther.-Nucleic Acids 2021, 23, 1–12. [Google Scholar] [CrossRef]
  111. Yao, B.; Zhang, Q.; Yang, Z.; An, F.; Nie, H.; Wang, H.; Yang, C.; Sun, J.; Chen, K.; Zhou, J.; et al. CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA. Mol. Cancer 2022, 21, 140. [Google Scholar] [CrossRef] [PubMed]
  112. Chen, T.; Hao, Y.; Zhang, Y.; Li, M.; Wang, M.; Han, W.; Wu, Y.; Lv, Y.; Hao, J.; Wang, L.; et al. m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency. Cell Stem Cell 2015, 16, 289–301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Sun, J.; Ma, X.; Ying, Y.; Wang, W.; Shen, H.; Wang, S.; Xie, H.; Yi, J.; Zhan, W.; Li, J.; et al. SMAD3 and FTO are involved in miR-5581-3p-mediated inhibition of cell migration and proliferation in bladder cancer. Cell Death Discov. 2022, 8, 199. [Google Scholar] [CrossRef] [PubMed]
  114. Nagahashi, M.; Shimada, Y.; Ichikawa, H.; Kameyama, H.; Takabe, K.; Okuda, S.; Wakai, T. Next generation sequencing-based gene panel tests for the management of solid tumors. Cancer Sci. 2019, 110, 6–15. [Google Scholar] [CrossRef] [Green Version]
  115. Sarkar, A.; Gasperi, W.; Begley, U.; Nevins, S.; Huber, S.M.; Dedon, P.C.; Begley, T.J. Detecting the epitranscriptome. Wiley Interdiscip. Rev. RNA 2021, 12, e1663. [Google Scholar] [CrossRef]
  116. Wei, J.; Yu, X.; Yang, L.; Liu, X.; Gao, B.; Huang, B.; Dou, X.; Liu, J.; Zou, Z.; Cui, X.L.; et al. FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development. Science 2022, 376, 968–973. [Google Scholar] [CrossRef]
  117. Selmi, T.; Lanzuolo, C. Driving Chromatin Organisation through N6-methyladenosine Modification of RNA: What Do We Know and What Lies Ahead? Genes 2022, 13, 340. [Google Scholar] [CrossRef]
Ijms 24 00773 g001 550
Figure 1. Regulatory proteins involved in mediating the m6A modification. m6A modification is synergistically catalyzed by methyltransferases (Writers), demethylases (Erasers) and methyl-binding proteins (Readers). The formation of m6A was initially catalyzed by a group of complexes, in which METTL3 and METTL 14 act as the active center of methyltransferases and WTAP, RBM15/15B, VIRMA and ZC3H13 play the part of adaptor proteins. In addition, METL16, HAKAI and ZCCHC4 were evidenced to be independently catalyzed the formation of m6A modification. FTO, ALKBH5 and ALKBH3 have been identified as m6A demethylases and they remove m6A marks on RNAs in an independent manner. Readers, involving biological functions by recognizing m6A modifications, include the YTH family, HNRNP family, IGFBPP1/2/3, EIF3 and ABCF1.
Figure 1. Regulatory proteins involved in mediating the m6A modification. m6A modification is synergistically catalyzed by methyltransferases (Writers), demethylases (Erasers) and methyl-binding proteins (Readers). The formation of m6A was initially catalyzed by a group of complexes, in which METTL3 and METTL 14 act as the active center of methyltransferases and WTAP, RBM15/15B, VIRMA and ZC3H13 play the part of adaptor proteins. In addition, METL16, HAKAI and ZCCHC4 were evidenced to be independently catalyzed the formation of m6A modification. FTO, ALKBH5 and ALKBH3 have been identified as m6A demethylases and they remove m6A marks on RNAs in an independent manner. Readers, involving biological functions by recognizing m6A modifications, include the YTH family, HNRNP family, IGFBPP1/2/3, EIF3 and ABCF1.
Ijms 24 00773 g001
Ijms 24 00773 g002 550
Figure 2. Schematic diagram of the mechanisms of m6A modification and its regulatory proteins regulating miRNA production.
Figure 2. Schematic diagram of the mechanisms of m6A modification and its regulatory proteins regulating miRNA production.
Ijms 24 00773 g002
Ijms 24 00773 g003 550
Figure 3. Schematic diagram of the mechanisms showing that m6A modification and its biological effects are regulated by miRNAs.
Figure 3. Schematic diagram of the mechanisms showing that m6A modification and its biological effects are regulated by miRNAs.
Ijms 24 00773 g003
Ijms 24 00773 g004 550
Figure 4. Mutual regulation between m6A modifications and miRNAs. The red and green arrows represent the level rise and fall, respectively. The purple arrows point to the regulated object. EC: esophageal cancer; TC: thyroid cancer; BRC: breast cancer; GC: gastric cancer; HCC: hepatocellular carcinoma; CRC: colorectal cancer; RCC: Renal cell carcinoma; BLC: bladder cancer; EOC: epithelial ovarian cancer; NSCLC: non-small cell lung cancer; LUAD: lung adenocarcinoma; PAC: pancreatic cancer; PDAC: Pancreatic ductal adenocarcinoma; PCa: prostate cancer.
Figure 4. Mutual regulation between m6A modifications and miRNAs. The red and green arrows represent the level rise and fall, respectively. The purple arrows point to the regulated object. EC: esophageal cancer; TC: thyroid cancer; BRC: breast cancer; GC: gastric cancer; HCC: hepatocellular carcinoma; CRC: colorectal cancer; RCC: Renal cell carcinoma; BLC: bladder cancer; EOC: epithelial ovarian cancer; NSCLC: non-small cell lung cancer; LUAD: lung adenocarcinoma; PAC: pancreatic cancer; PDAC: Pancreatic ductal adenocarcinoma; PCa: prostate cancer.
Ijms 24 00773 g004
Table
Table 1. m6A modification involves in regulation of miRNA expression.
Table 1. m6A modification involves in regulation of miRNA expression.
Regulatory Proteins of m6Am6A on RNAsmiRNAs Affected by m6AMechanisms of m6A Mediating miRNAsDiseasesRef.
METTL14↓pri-miR-126↑miR-126↓M6A modification reduced recognition of pri-miR-126 by DGCR8Pulmonary fibrosis[18]
METTL3↓-70% miRNAs↓METTL3 catalyzed m6A modification on pri- miRNAs, thus promoting them for recognition and processing by DGCR8 -[57]
METTL3↑-miR-25-3p↑METTL3 catalyzed the formation of m6A modification on pri-miR-25 to promote its processing via NKAPPancreatic cancer[59]
METTL3↓METTL14↓pri-miR-126↑miR-126↓Reduction of m6A modification weakened recognition of pri-miR-126 by DGCR8Hepatocellular carcinoma[60]
METTL3↓-miR-873-5p↓METTL3 interacted with DGCR8 and positively modulates maturation of miR-873-5pKidney injury[61]
METTL3↑pri-miR-365-3p↑-METTL3 positively affected the interaction between DGCR8 and pri-miR-365 Chronic inflammatory pain[62]
METTL3↑pri-miR-221/222↑-METTL3 positively modulated the pri-miR221/222 processing through interacting with DGCR8Bladder cancer[63]
METTL3↑-miR-21-5p↑Up-regulation of METTL3 promoted maturation of miRNA-21-5p Obstructive renal fibrosis[65]
METTL3↑pre-miR-143-3p↓miR-143-3p↑Knockdown of dicer can abolish METTL3-induced up-regulation of miR-143-3p Lung cancer[67]
METTL3↓pre-miR-320↑miR-320↑METTL3 enhanced the m6A methylations on pre-miR-320 Osteoporosis[68]
METTL14↓-miR-130a-3p↑ miR-130b-3p↑ miR-106b-5p↑ miR-301a-3p↑MiRNA levels negative correlation with METTL14 mRNAKidney renal clear cell carcinoma[71]
METTL3↑pri-miR-1246↑-METTL3 methylated and promoted pri-miR-1246 maturation Colorectal cancer[69]
METTL3↑Total RNAs9 miRNAs↑miRNA level positive correlation with METTL3 levelMalignant transformation[70]
METTL3↑E2F3 mRNAmiR-660↓m6A-modified E2F3 mRNA was required for the interaction between miR-660 and METTL3Gastric cancer[87]
ALKBH5↓-miR-107↑miR-107 level negative correlation with ALKBH5Non-small cell lung cancer[75]
ALKBH5↓-miR-194-2↑ALKBH5 inhibited miR-194-2 biogenesis through an m6A/DGCR8-dependent mannerEsophageal cancer malignancy[76]
ALKBH5↑-miR-21-5p↑ALKBH5 changed the miR-21-5p silencing potency by altered the m6A abundanceNon-small cell lung cancer cells[77]
ALKBH5↑Pri-miR-320a-3p↑miR-320a-3p↓ALKBH5 promoted lung fibrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1Lung fibrosis[78]
FTO↓miRNAs42 miRNAs↑9 miRNAs↓FTO affected the modification of m6A on mature miRNA-[72]
FTO↑-miR-181b-3p↓FTO promoting breast cancer via the FTO/miR-181b-3p/ARL5B pathwayBreast cancer[73]
FTO↑-miR-576↓FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathwaysBladder cancer[74]
HNRNPA2B1↑-miR-29a-3↓miR-29b-3↓miR-222↓ miR-1266-5↑miR-1268a↑miR-671-3p↑HNRNPA2/B1 promoteed DROSHA processing to pre-miRNAsBreast cancer[81]
HNRNPA2B1↑pri-miR-106b-5p↑MiR-106b-5p↑HNRNPA2B1 inhibited SFRP2 and activated Wnt-β/catenin via m6A-mediated miR-106b-5p processing to aggravate steaminess in lung adenocarcinomaLung adenocarcino-ma[84]
IGF2BP1 ↑-miR-22-3p↓miR-125-5p↓miR-181-5p↓, etc.IGF2BP1 impaired the miRNA-directed down regulation of SRF expressionOvarian, liver and lung cancer[86]
YTHDC1↓Pri-miR-30d↑miR-30d↓YTHDC1 induced miR-30d function as a tumor suppressor gene by negatively regulating RUNX1 and its downstream glycolytic genes including HK1 and SLC2A1Pancreatic ductal Adenocarcin-oma[79]
Note: Sections of table with blue, green and pink background describe the process of miRNA production regulated by methyltransferases, demethylases and methyl-binding proteins, respectively. The red upward arrow represents the elevation of expression, and the green downward arrow indicates the reduction of expression.
Table
Table 2. miRNAs involve in mediation the m6A modification.
Table 2. miRNAs involve in mediation the m6A modification.
miRNAsRegulatory Proteins of m6AMechanisms of miRNAs Regulate m6A LevelDiseasesRefs.
miR-33a↑METTL3↓MiR-33a targeted to the 3′-UTR of METTL3 mRNANon-small cell lung cancer[92]
miR-600↓METTL3↑MiR-600 inhibited the expression of METTL3Lung cancer[93]
miR-4429↑METTL3↓MiR-4429 targeted and inhibited METTL3 levelGastric cancer[95]
let-7g↓METTL3↑Suppressing let-7g thus up-regulating METTL3Breast cancer[96]
miR-186↓METTL3↑Low level of miR-186 led to high expression of METTL3Hepatocellular carcinoma[97]
miR-320d↓METTL3↑MiR-320d inhibits KIF3C expression by targeting METTL3 Prostate cancer[98]
miR-1269b↓mir-338-5p↓METTL3↑METTL3 was the direct target of miR-1269b and miR-338-5pGastric cancer[90,91]
miR-524-5P↓METTL3↑CircVMP1 plays an oncogenic role by targeting miR-524-5p-METTL3/SOX2 axis in A549/DDP and H1299/DDP cells.Non-small cell lung cancer[94]
miR-16-1-3p↑miR-101a-3p↑miR-362-5p↑miR-501-5p↑ miR-532-3p↑miR-542-3p↑METTL14↓MiRNAs were all predicted to regulate METTL14 mRNAMEHP toxicity[99]
miR-193a-3p↓ALKBH5↓MiR-193a-3p targeted to ALKBH5 by suppressing the AKT2 pathwayGlioma cells[100]
miR-4739↑FTO↓CircGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loopHepatocellular carcinoma[101]
miR-155↑FTO↓MiR-155 directly targeted FTO and negatively regulated its expression and increased m6A levelRenal cell carcinoma[102]
miR-421-3p↓YTHDF1↑MiR-421-3p suppresses inflammatory response during cerebral I/R injury through regulating YTHDF1/P65Cerebral I/R injury[103]
miR-376c↓YTHDF1↑YTHDF1 overexpression reversed the inhibitory role of miR-376c released by EC-Evs in NSCLC cellsNon-small cell lung cancer[104]
miR-145↓YTHDF2↑MiR-145 decreased the luciferase activities of 3′-UTR of YTHDF2 mRNAHepatocellular carcinoma[105]
miR-145↓YTHDF2↑YTHDF2 was the direct target gene of miR-145Epithelial ovarian cancer[106]
miR-6125↓YTHDF2↑MiR-6125 targeted the 3′-UTR of YTHDF2 and downregulated the YTHDF2 proteinColorectal cancer[108]
miR-495↓YTHDF2↑MiR-495 can inhibit the proliferation, invasion and migration of PCa cells by targeting YTHDF2Prostate cancer[107]
miR-204↓IGF2BP2↑IGF2BP2 was a target of miR-204.Thyroid cancer[110]
miR-133b↓IGF2BP2↑CircEZH2 interacted with IGF2BP2 and served as a sponge of miR-133bColorectal cancer[111]
Note: Sections of table with blue, green and pink background describe the process of miRNA production regulated by methyltransferases, demethylases and methyl-binding proteins, respectively. The red upward arrow represents the elevation of expression, and the green downward arrow indicates the reduction of expression.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Mei, Z.; Mou, Y.; Zhang, N.; Liu, X.; He, Z.; Gu, S. Emerging Mutual Regulatory Roles between m6A Modification and microRNAs. Int. J. Mol. Sci. 2023, 24, 773. https://doi.org/10.3390/ijms24010773

AMA Style

Mei Z, Mou Y, Zhang N, Liu X, He Z, Gu S. Emerging Mutual Regulatory Roles between m6A Modification and microRNAs. International Journal of Molecular Sciences. 2023; 24(1):773. https://doi.org/10.3390/ijms24010773

Chicago/Turabian Style

Mei, Zongqin, Yahao Mou, Nan Zhang, Xiaoyu Liu, Zuoshun He, and Shiyan Gu. 2023. "Emerging Mutual Regulatory Roles between m6A Modification and microRNAs" International Journal of Molecular Sciences 24, no. 1: 773. https://doi.org/10.3390/ijms24010773

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop