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. Author manuscript; available in PMC: 2021 Mar 28.
Published in final edited form as: Methods Enzymol. 2020 Mar 28;637:283–308. doi: 10.1016/bs.mie.2020.02.009

Retinoic acid and microRNA

Lijun Wang 1, Atharva Piyush Rohatgi 1, Yu-Jui Yvonne Wan 1,*
PMCID: PMC7445077  NIHMSID: NIHMS1620338  PMID: 32359650

Abstract

Retinoic acid (RA), the biologically active metabolite of vitamin A, regulates a vast spectrum of biological processes, such as cell differentiation, proliferation, apoptosis, and morphogenesis. microRNAs (miRNAs) play a crucial role in regulating gene expression by binding to messenger RNA (mRNA) which leads to mRNA degradation and/or translational repression. Like RA, miRNAs regulate multiple biological processes, including proliferation, differentiation, apoptosis, neurogenesis, tumorigenesis, and immunity. In fact, RA regulates the expression of many miRNAs to exert its biological functions. miRNA and RA regulatory networks have been studied in recent years. In this manuscript, we summarize literature that highlights the impact of miRNAs in RA-regulated molecular networks included in the PubMed.

1. Introduction

Retinoic acid (RA) is a metabolite of vitamin A that has a vast spectrum of biological processes, including differentiation, proliferation, apoptosis, and morphogenesis (Hu, Xu, Sun, Teng,& Xiao, 2017;Wang et al., 2012). While all-trans-RA is a major form, other isomers such as 13-cis-RA and 9-cis-RA are also present (Ruhl, Krezel, & de Lera, 2018; Tang & Russell, 1990). In this paper, RA is used to refer to all-trans-RA. Pharmacologically, retinoids including RA are used for acne and cancer treatment (Dobrotkova, Chlapek, Mazanek, Sterba, & Veselska, 2018; Leyden, Stein-Gold, & Weiss, 2017). Its effects in treating inflammation, allergy, and autoimmune diseases have also been revealed (Oliveira, Teixeira, & Sato, 2018).

The action of RA is mediated through the nuclear receptors: retinoic acid receptor (RARα, β, and γ) and retinoid x receptors (RXRα, β, and γ). Because RXR is an essential partner of many nuclear receptors, RA can regulate the function of other nuclear receptors such as peroxisome proliferator activate receptor and farnesoid x receptor. This allows RA to regulate lipid metabolism (Bushue & Wan, 2010; Chen, Wang, & Wan, 2010; Dai et al., 2003; Goto, 2019; Gyamfi, He, French, Damjanov, & Wan, 2008; Hu et al., 2017; Krezel, Ruhl, & de Lera, 2019; Liu, Wang, & Lin, 2019; Martin, Ma, & Bernard, 2019; Ruhl et al., 2018; Wan et al., 2000, 2000, 2003; Watanabe & Kakuta, 2018). Many RAR and RXR-regulated genes have been identified using genome-wide approaches such as chromatin immunoprecipitation followed by sequencing (Al Tanoury et al., 2014; Fang et al., 2013; He et al., 2013; Hu et al., 2013; Hua, Kittler, & White, 2009; Kiss et al., 2017; Liu, Ly, Hu, & Wan, 2014; Penvose, Keenan, Bray, Ramlall, & Siggers, 2019; Tang et al., 2011). In addition to transcriptional regulation, oral administration of RA alters gut microbiota and has an impact on liver regeneration (Liu, Hu, & Wan, 2016). Thus, it is important to understand mechanisms by which RA exerts its effects.

miRNA is small non-coding RNA that silences messenger RNA (mRNA). Its functions via base-pairing with complementary sequences within mRNA. As a result, the targeted mRNA is reduced by either cleavage or destabilization, or has its translational efficiency reduced (Fig. 1). miRNAs regulate the expression of as much as one-third of human gene-encoded proteins (Ganapathy & Ezekiel, 2019). Like RA, miRNAs regulate multiple biological and disease processes (Ganapathy & Ezekiel, 2019; Ivey & Srivastava, 2015). miRNAs have been approved by the FDA as diagnostic tools and for treatment (Dave et al., 2019). This review paper focuses on the miRNAs that mediate or affect the effects of RA. In some cases, RA regulates the expression of miRNA through its receptors such as RARα and RARβ, which bind to the regulatory region of certain miRNAs to alter their expression levels. In other cases, miRNA may target the receptors of RA and affect the effect of RA (Fig. 2). The literature search was limited to the papers included in the PubMed using mammalian cells or animal models.

Fig. 1.

Fig. 1

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miRNA Biogenesis. miRNA is transcribed into pri-mRNA, which is converted to pre-miRNA by the protein complex Drosha-Pasha. Pre-miRNA is then transported out of the nucleus via the protein exportin 5. The endoribonuclease dicer cleaves pre-miRNA to form a miRNA duplex. Then, unwinding of the two strands and asymmetric assembly of one strand into RISC (RNA-induced silencing complex) occurs. The RISC complex acts via transcriptional silencing, reduced translational efficiency, or mRNA degradation.

Fig. 2.

Fig. 2

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Retinoic acid and its receptor-mediated gene expression. RA is transported into the cell and bind to CRABP2 (cellular RA binding protein). In the nucleus, RA binds to nuclear receptors RXR and RAR heterodimer, which recognizes the RA receptor responsive element (RARE) located on the target gene, to regulate gene expression. The transcriptional activation requires the recruitment of coactivators and the departure of co-suppressors. Once miRNA is produced, it can silence the RA receptors, the transcriptional co-regulators, or other specific targets to modulate the effects of RA.

2. miRNAs that are implicated in RA-induced differentiation

2.1. Embryonic stem cell differentiation

Dicer is an endoribonuclease that cleaves double stranded RNA critical for miRNA biogenesis. In Dicer-deficient embryonic stem cells, increased dimethylation of histone H3 at lysine 9 (H3K9me2) at over 900 CpG islands has been noted, indicating the significance of miRNAs in epigenome regulation during differentiation. Additionally, the balance between the transcriptionally favorable tri-methylation histone H3 at lysine 4 (H3K4me3) and the unfavorable tri-methylation histone H3 at lysine 27 (H3K27me3) is shifted in the Dicer-deficient epigenome. Homeobox (HOX) transcription factors play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. In response to RA treatment, elevated H3K27me3 is found in the promoters of the caudal type homeobox 2 (Cdx2) and homeobox A1 (Hoxa1) genes of Dicer-deficient embryonic stem cells. However, forced expression of let-7g in Dicer-deficient embryonic cells counteracts the effect of H3K27me3 on the expression of the Cdx2 and Hoxa1 genes. Let-7g counteracts the effects by reducing the enhancer of zeste homolog 2(Ezh2), a histone-lysine N-methyltransferase enzyme, which thereby leads to the differentiated phenotype (Tennakoon, Wang, Coarfa, Cooney, & Gunaratne, 2013).

miRNAs inhibit mouse embryonic stem cell self-renewal and stabilize their differentiated states. In mouse embryonic stem cells, RA upregulates miRNA-134, miR-296, and miR-470, which induces differentiation by targeting the pluripotency genes Nanog, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2) (Tay et al., 2008; Tay, Zhang, Thomson, Lim, & Rigoutsos, 2008). miRNA-134 inhibits Nanog and the liver receptor homolog 1 (LRH1), both of which positively regulate Oct4 (Tay, Tam, et al., 2008). In addition, miR-134, miR-296, and miR-470 are all involved in the lineage specific repression of mouse embryonic stem cell renewal (Zhang et al., 2015). Elevated forkhead box protein M1 (FOXM1) contributes to the maintenance of human stem cell pluripotency by directly regulating the Oct4 promoter. miR-134 over-expression reduces FOXM1 and promotes the differentiation effect of RA (Chen et al., 2015). Additionally, by reducing either miR-200b or miR-200c, RA inhibits the expression of pluripotency genes and increases the ectodermal marker Nestin, a type VI intermediate filament protein (Zhang, Gao, et al., 2015).

2.2. Neuronal differentiation

The significance of miR-10 in neuronal differentiation has been revealed. The hsa-miR-10 family is substantially increased (~95-fold) during the RA-induced neuronal differentiation of human embryonic stem cells (Parsons, 2012). In addition, during RA-induced neural lineage specific progression, hsa-miR-302 family is reduced and the expression of the Hox gene, hsa-miR-10, and let-7 are induced (Parsons, Parsons, & Moore, 2012). Similarly, the expression of Hoxd4 and miR-10b is coordinated in the RA-induced neural differentiation of P19 cells. This suggests the importance of miR-10b (Phua et al., 2011). Through the let-7-dependent mechanism, phosphorylation of a highly conserved RNA-binding protein called LIN28A fosters neural differentiation of P19 cells (Liu et al., 2017). Moreover, the differentiation of embryonic stem cells is also accompanied with increased miR-10a-5p, miR-219–5p, and miR-219-2-3p. The increase of miR-219 and its mimics also promote mouse embryonic stem cell differentiation into neural cells (Wu et al., 2017). In contrast, miR-125b-2 over-expression suppresses this differentiation (Deng, Zhang, Xu, & Ma, 2015).

Sirtuin 1 (SIRT1) plays a negative role in inducing the differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells. When SIRT1 is inhibited, the differentiation continues and is marked by increased miR-34a, which silences SIRT1 (Hu et al., 2014). In mouse neuroblastoma N2a cells, P19 embryonal carcinoma cells, and the mouse brain, increased miR-124 reduces RARγ, thereby inhibiting neurite outgrowth (Wang, Yao, Lu, Li, & Ma, 2010) (Su, Gu, Zhang, Li, & Wang, 2020). There are many other miRNAs that may be implicated in neural cell differentiation (Hu et al., 2017). RA treatment of adipose-derived mesenchymal stem cells leads to changes in 76 miRNAs that have a greater than twofold difference (Hu et al., 2017).

2.3. Spermatogonia differentiation

Tyrosine-protein kinase Kit, a receptor tyrosine kinase protein, plays an essential role in cell proliferation, hematopoiesis, etc. The tyrosine-kinase receptor Kit is also essential for the maintenance of primordial germ cells in both sexes, and RA-induced differentiation of spermatogonia is accompanied by Kit induction. Recent data reveals that RA-induced miR-26b promotes the transition from Kit-negative to Kit-positive spermatogonia (Tu et al., 2018). miR-26b can silence a transcriptional factor named promyelocytic leukemia zinc finger protein (Plzf) in undifferentiated spermatogonia. It also downregulates the methylcytosine dioxygenase (Tet3) gene, thus reducing 5-hydroxymethylcytosine in spermatogonia. Together, through various mechanisms including epigenetic regulation, RA regulates spermatogonia differentiation (Tu et al., 2018).

While glial cell-derived neurotrophic factor (GDNF) is essential for the self-renewal of spermatogonia stem cells, RA is critical for the differentiation of spermatogonia. miR-202–3p, which is abundantly found in the testis, can be induced by GDNF but is reduced by RA. miR-202–3p prevents stem cells from premature differentiation by suppressing RNA binding fox-1 homolog 2 (Rbfox2). In addition, the inhibition of miR-202–3p, but not of miR-202–5p, induces the differentiation of spermatogonia stem cells (Chen et al., 2017).

RA-induced differentiation of spermatogonia has reduced miR-146, which targets the mediator complex subunit 1 (Med1), a co-activator of RARs and RXRs. miR-146 can also inhibit the expression of stimulated by retinoic acid 8 (Stra8) and the spermatogenesis- and oogenesis-specific basic helix-loop-helix 2 (Sohlh2) (Huszar & Payne, 2013). Thus, RA-reduced miR-146 is critically important for RA-induced differentiation of spermatogonia. In addition, RA also reduces miR-17–92 (Mirc1) and miR-106b-25 (Mirc3), both of which function cooperatively to promote mouse spermatogonia differentiation (Tong, Mitchell, McGowan, Evanoff, & Griswold, 2012).

2.4. Pre-adipocytes and myoblast differentiation

RA inhibits the differentiation of 3T3-L1 pre-adipocytes by reducing lipid metabolism (Stoecker, Sass, Theis, Hauner, & Pfaffl, 2017). Such an action is through miR-27a and miR-96 induction that leads to the rearrangement of the actin cytoskeleton as well as inhibition of the citric acid cycle (Stoecker et al., 2017).

Excess RA also inhibits myoblast differentiation and proliferation. In an embryonic tongue-derived myoblast C2C12 cell line, RA induce miR-27b-3p, which silences the α-dystrobrevin (DTNA) gene to inhibit proliferation and differentiation (Li et al., 2017). In addition, RA-induced miR-31–5p targets the Ca2+/calmodulin-dependent protein kinase II δ gene (CamkIIδ) and is implicated in the RA-induced myogenic abnormalities of tongue (Liu et al., 2017). miR-133a, 210, and 34a are also involved in the RA-induced myoblasts differentiation and proliferation (Vecellio et al., 2012).

miR-10a targets the histone deacetylase 4 (Hdac4) gene and has a critical role in the RA-induced differentiation of mouse embryonic stem cells into smooth muscle cells (Huang et al., 2010). In addition, nuclear factor kappa B (NFκB), through binding to the miR-10a promoter, has a significant role in the differentiation process. Inhibiting the nuclear translocation of NFκB reduces miR-10a and prevents the RA-induced differentiation smooth muscle cells (Huang et al., 2010).

2.5. Hematopoietic progenitor cell differentiation

RA induces miR-223, which acts as a translational inhibitor to regulate lineage specification and differentiation of mouse hematopoietic stem cells (Chen, Li, Lodish, & Bartel, 2004). Transcription factors nuclear factor I-A (NFI-A) and CCAAT/enhancer-binding protein-alpha (C/EBPα) compete for binding to the miR-223 promoter. In response to RA treatment, the induction of miR-223 requires the release of NF1-A and the binding of C/EBPα. Taken together, the RA regulated differentiation of granulocytes is mediated by miR-223 expression controlled by two transcriptional factors (Fazi et al., 2005).

3. miRNAs that are implicated in RA-regulated inflammatory signaling and immunity

Signal-regulatory protein α (SIRPα) is essential for modulating leukocyte inflammatory responses. The SIRPα gene is a commonly targeted by miR-17, miR-20a, and miR-106a. RA reduces these miRNAs and increases SIRPα expression in SIRPα-negative promyelocytic cells. However, bacterial lipopolysaccharides (LPS) increases miR-17, miR-20a, and miR-106a in macrophages, which leads to SIRPα reduction and macrophage activation. Thus, miR-17, miR-20a, and miR-106a regulate macrophage inflammatory responses by repressing SIRPα. (Zhu et al., 2013).

RA-induced miR-10a is abundantly found in naturally occurring regulatory T cells (Treg). miR-10a inhibits the development of inducible T regulatory cells (iTregs) into follicular helper T cells by suppressing both the transcriptional repressor B-cell lymphoma 6 (Bcl6) and the co-repressor nuclear receptor co-repressor 2 (Ncor2). In addition, miR-10a attenuates the differentiation process into the T(H)17 subset of helper T cells (Takahashi et al., 2012). In contrast to RA, transforming growth factor-β (TGF-β)-induced iTregs in vitro are unstable and do not have miR-10a. Thus, RA-induced miR-10a is selectively expressed and plays a role in stabilizing iTregs (Jeker et al., 2012).

T-cell receptor (TCR) signaling and TGF-β regulate the production of peripheral regulatory T (pTreg) cell. The expression of miR-31 is triggered by TCR signaling but inhibited by TGF-β. miR-31 directly targets the retinoic acid-inducible protein 3 (Gprc5a), a member of the type 3G protein-coupled receptor family. The deficiency of this protein leads to the impairment of pTreg-cell induction as well as an increased severity of experimental autoimmune encephalomyelitis (Zhang et al., 2015). Therefore, by targeting Gprc5a, miR-31 reduces the production of pTreg (Zhang, Ke, et al., 2015).

RA induces the secretion of exosomes in gut-tropic T cells that causes an upregulation of integrin α4β7 that binds to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). Addressins are the ligands to the homing receptors of lymphocytes, which determine which tissue the lymphocyte will enter. miRNA profiling suggests that exosomes that originate from the gut tropic T cells contain a large quantity of miRNAs, such as miR-132 and miR212, which target NKX2.3, a transcription factor important for the expression of MAdCAM-1 (Park et al., 2019).

Metabolism controls immune cell fate and function. miR-33 not only represses genes involved in cholesterol efflux and fatty acid oxidation, but also polarization of immune cells. Macrophage-specific miR-33 deletion promotes M2 macrophage polarization. Interestingly, inhibiting miR-33 enhances the expression of RA-producing enzyme aldehyde dehydrogenase family 1, subfamily A2 (ALDH1A2), as well as the activity of retinal dehydrogenase in macrophages. Such findings are in consistent with the ability of RA to foster iTregs. Furthermore, treating hypercholesterolemic mice with miR-33 inhibitors leads to accumulation of inflammation-suppressing M2 macrophages and forkhead box P3+ (foxp3+) Tregs in plaques. This treatment thereby inhibits the progression of atherosclerosis. Together, inhibiting miR-33 benefits metabolism and inflammation (Ouimet et al., 2015).

4. miRNAs that are implicated in RA-induced differentiation of cancer cells

4.1. Embryonic carcinoma

RA has a profound effect in inducing the differentiation of embryonic carcinoma F9 cells into endodermal cells (Wan, Orrison, Lieberman, Lazarovici, & Ozato, 1987; Wan, Wang, & Wu, 1994; Wu, Wang, & Wan, 1992). In the F9 cell line, RA induces miR-485, which silences the α/β-hydrolase domain-containing protein 2 (Abhd2). The reduction of Abhd2 leads to ERK1/2 phosphorylation and differentiation of embryonic carcinoma cells (Yu, Zhang, Liu, Liu, & Guo, 2019).

4.2. Brain tumors

RA treatment enhances gap junctions which leads to an increased miR-124–3p-mediated antiproliferation in glioblastoma cells (Suzhi et al., 2015). RA also induces glioma cell death by elevating miR-302b, and silences E2F3, a transcriptional glioma growth regulator (Chen et al., 2014). In addition, reduced miR-452 found in gliomas promotes their stem-like features and tumorigenesis because miR-452 inhibits many stemness regulators like polycomb complex protein BMI-1, lymphoid enhancer binding factor 1 (LEF1), and transcription factor 4 (TCF4), (Liu et al., 2013).

4.3. Neuroblastoma

Several miRNAs have changes in their expression levels when the human neuroblastoma cell line SH-SY5Y is treated with RA and a dopamine cocktail (Das & Bhattacharyya, 2014). Among them, miR-432 plays a key role in differentiation of human neuroblastoma cells by suppressing NESTIN and the repressor element-1-silencing transcription factor (REST) corepressor 1 (RCOR1) (Das & Bhattacharyya, 2014). RA induces neuronal differentiation via miR-29b and miR-664a-5p (Jauhari, Singh, & Yadav, 2018; Watanabe, Yamaji, & Ohtsuki, 2018). miR-29b reduces the P53 inhibitor P85α, which in turns increases miR-145 to silence OCT4, SOX2, and kruppel-like factor 4 (KLF4) during SH-SY5Y differentiation (Jauhari et al., 2018). Further studies are required to understand the function of miR-664a-5p (Watanabe et al., 2018).

RA has anti-metastatic and anti-migratory activities via miR-10a and miR-10b, both of which target the SR-family splicing factor SFRS1 (SF2/ASF) (Meseguer, Mudduluru, Escamilla, Allgayer, & Barettino, 2011). They also induce neuronal differentiation by silencing NCOR2 which inhibits neurite growth (Foley et al., 2011). Moreover, other RA-induced miRNAs, including miR-9 and miR-103, control neuroblastoma differentiation by reducing a differentiation inhibitor molecule called Inhibitor of DNA-binding 2 (Id2) (Annibali et al., 2012). RA can also decrease miR-17 in SH-SY5Y cells. miR-17 is involved in the regulation of the mitogen-activated protein kinase (MAPK) signaling pathway, synaptic plasticity, and other markers of neuronal differentiation (Beveridge, Tooney, Carroll, Tran, & Cairns, 2009). RA- and brain-derived neurotrophic factor (BDNF)-induced miR-125b and miR-124a also positively regulate the differentiation of SH-SY5Y cells and neurite outgrowth of human neural progenitor ReNcell VM cells by targeting multiple genes (Le et al., 2009).

The mutant amyloid precursor protein (APP)L17C [the leucine (L) residue 17 is replaced by a cysteine (C) residue in amyloid β peptide (Aβ)] increases amyloid precursor protein dimerization which leads to reduced neurite outgrowth. The overexpression of a mutant amyloid precursor protein (APP)L17C in human neuroblastoma SH-SY5Y cells inhibits neurite outgrowth (Luu et al., 2019). miR-34a expression is greatly decreased in APPL17C compared to APPWT cells, and overexpression of miR-34a restores neurite outgrowth in the mutant cells (Luu et al., 2019). Thus, miR-34a expression has a pivotal role in APP-mediated neurite outgrowth (Luu et al., 2019).

DNA demethylation mediated by miRNAs promotes RA-induced differentiation of neuroblastoma cells. The ectopic overexpression of miR-152 that targets the DNA methyltransferase 1 (DNMT1), contributes to the differentiated phenotypes, including reduced invasiveness and anchorage-independent growth in a human neuroblastoma cell line SK-N-BE (Das et al., 2010).

Other miRNAs are implicated in the differentiation of neuroblastoma cells. During the differentiation of NT2 cells, the stemness phenotype-associated miR-302 is reduced, but let-7, miR-125b, and miR-132 are increased (Pallocca et al., 2013). miR-128 is also increased that in turn reduces Reelin and Doublecortin, where both are involved in the migratory potential of neural cells (Evangelisti et al., 2009). Moreover, during the RA-induced differentiation of neuroblastoma BE (2)-C cells, tumor suppressor miR-449a is increased. miR-449a targets the microfibril associated protein 4 (MFAP4), plakophilin 4 (PKP4), and TRNA splicing endonuclease subunit 15 (TSEN15), which are associated with poor survival of neuroblastoma patients (Zhao et al., 2015). Moreover, miR-449a induces cell cycle arrest by inhibiting the cyclin dependent kinase 6 (CDK6) and lymphoid enhancer binding factor 1 (LEF1) (Zhao et al., 2015).

RA-induced differentiation of the human neuroblastoma SK-N-BE cells have overexpressed miR-34a that directly targets the E2F3 and lowers its protein. E2F3 is a potent transcriptional inducer for cell-cycle progression. In addition, overexpression of miR-34a in neuroblastoma cell lines prevents cell proliferation by inducing the caspase-dependent apoptotic pathway. Furthermore, miR-34a is reduced in primary neuroblastoma tumors and cell lines when compared to normal adrenal tissue (Welch, Chen, & Stallings, 2007). miR-184 is also implicated in the apoptosis pathway as RA-induced miR-184 promotes the apoptosis of human neuroblastoma cell lines including KELLY or SK-N-AS (Chen & Stallings, 2007).

4.4. Hematopoietic malignancies

Acute promyelocytic leukemia (APL) is caused by translocation of the promyelocytic leukemia (PML) gene located on chromosome 15 and the RARα gene on chromosome 17, which generates a fusion oncogene PML/RARα and differentiation arrest.

In hematopoietic malignancies, high c-Myc expression is correlated with a poor prognosis (Delgado & Leon, 2010). It has been shown that reduced PML/RARα due to loss of c-Myc is miRNA-dependent. In addition, tumor suppressor let-7 has been identified to target both the c-Myc and the PML/RARα (Ding et al., 2016). Moreover, PML/RARα binds to the RA responsive element of the host genes such as the let-7c (Careccia et al., 2009; Pelosi et al., 2014). However, RA treatment induces a conformational change in the host promoter thus regulating let-7c (Pelosi et al., 2014). Taken together, RA by inducing let-7c, which silences PML/RARα, can lead to the differentiation of APL (Ding et al., 2016).

The synergism between c-Myc and miR-17–19b, a truncated version of the miR-17–92 cluster, is well-established for tumor initiation (He et al., 2005; Mu et al., 2009). RA not only reduces c-Myc mRNA but also miR-17–92 to induce APL cell differentiation (Yu et al., 2019). In the APL NB4 cell line, RA induces miR-10b, miR-194, miR-195, miR-196a, and others. Many of them are transcriptionally silenced by PML/RARα which leads to oncogenesis (Saumet et al., 2009). To add on, a long non-coding RNA named HOTAIRM1 increases the RA-induced degradation of PML/RARα via the autophagy pathway. In fact, HOTAIRM1 can function as a miRNA sponge to regulate the expression of autophagy-related genes by competing for miRNA bindings sites (Chen et al., 2017).

Other mechanisms are involved in RA-mediated differentiation of APL. Knockdown adenylate cyclase 9 (ADCY9), which converts ATP into cAMP, inhibits RA-induced differentiation of APL. Similarly, miR-181a, which directly targets ADCY9 and reduces cAMP, has a negative role in RA-induced APL differentiation (Zhuang et al., 2014). miR-17–5p also inhibits RA-induced APL cell differentiation (Yu, Hu, et al., 2019). In contrast, RA induces granulocytic differentiation through miR-382–5p that silences the suppressor gene phosphatase and tensin homolog (PTEN) (Liu et al., 2019).

By regulating miRNA, RA treats APL (van Gils, Verhagen, & Smit, 2017). RA treatment causes a loss of imprinting on chromosome 14q32 that regulates the overexpression of many miRNAs (Manodoro et al., 2014). RA treatment of APL cells increases many tumor suppressor miRNAs, such as the let-7 family (Garzon et al., 2007; van Gils et al., 2017). RA treatment of APL cells also increases miR-107, which silences the NFI-A (Fazi et al., 2005) (Garzon et al., 2007). RA also reduces many miRNAs such as miR-17 and miR-25 in APL cells (Garzon et al., 2007; Rossi et al., 2010). Moreover, by reducing miR-301a-3p to increase ubiquitin-specific protease 48 (USP48), RA is effective in APL differentiation (Li et al., 2018).

RA increases miR-145 in myeloid leukemia cells which thereby reduces RAS-responsive element-binding protein 1 (RREB1), which prevents granulocytic differentiation of myeloid leukemia cells (Yao et al., 2019). In addition, miR-29a, which targets the CDK6, and miR-142–3p, which silences the TGF-β-activated kinase 1/MAP3K7 binding protein 2 (TAB2), contributes to RA-induced granulocytic differentiation of HL-60, THP-1, or NB4 cells. Forced expression of either miR-29a or miR-142–3p in hematopoietic stem cells induces myeloid differentiation (Wang et al., 2012). Ectopic miR-638 overexpression, which targets the cyclin-dependent kinase 2 (CDK2), also increases RA-induced differentiation of leukemic cell lines and primary acute myeloid leukemia blasts (Lin et al., 2015). Moreover, RA increases the expression of tumor suppressor miR-663 and inhibits HL-60 cell proliferation. Exotic overexpression of miR-663 also induces HL-60 cell differentiation (Jian et al., 2011).

Autophagy regulated by miRNA has a role in the regulation of myeloid differentiation. Autophagy genes (ATG) are frequently repressed in primary acute myeloid leukemia patients. These reduced levels are likely due to increased miR-106a, which targets a transcriptional factor for several ATG genes (Jin et al., 2018). By mediating other mechanisms such as regulation of transcriptional machinery, miRNA is important for differentiation. In malignant myeloid cells, transcription factor CDX2 induces miR-125b expression. Increased miR-125b prevents the differentiation of myeloid cells and promotes leukemogenesis by inhibiting the core binding factorβ (CBFB) translation. RA treatment decreases CDX2 activity, reduces miR-125b, and increases the CBFB during myeloid cell differentiation and in patients. Thus, miR-125b is important for RA-induced differentiation (Lin et al., 2011).

HOXB4, which has a function in stem cell expansion, along with miR10a, is highly expressed in atypical myeloproliferative neoplasms. However, overexpression of miR-10a has no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. (Dumas et al., 2018). RA reduces HOXA9 in acute leukemia cells leading to the inhibition of proliferation and promotion of differentiation of leukemia cells. The downregulation also interferes with tumor growth by modulating certain miRNAs. For example, during the leukemia cell differentiation induced by HOXA9 downregulation, miR-663 and miR-494 are increased and miR-10a and miR-181 are decreased (Chen, Yu, Lv, & Zhang, 2017).

4.5. Breast cancer

Retinoids are promising for breast cancer prevention and treatment. In estrogen receptor (ER)-positive breast carcinoma cells (MCF-7), RA induces miR-21 to counteract the anti-proliferative action of RA but may have a benefit in reducing cell motility. The pro-inflammatory cytokine IL1B, the adhesion molecule ICAM-1, and the tissue-type plasminogen activator (PLAT) are the identified miR-21 target genes (Terao et al., 2011). In addition, miR-21 targets the tumor suppressor gene tropomyosin 1 (TPM1) that is implicated in cell migration, as well as the programmed cell death 4 (PDCD4), and the mammary serine protease inhibitor (Maspin) (Terao et al., 2011). Thus, miR-21 inhibitors may be used for breast cancer treatment.

Other miRNAs are implicated in RA-mediated anti-breast cancer effects. Nearly 70% of human breast carcinomas have reduced HOXA5. In addition, loss of HOXA5 in human breast cancer correlates with the progression to higher-grade lesions, suggesting its tumor suppressor effect (Jeannotte, Gotti, & Landry-Truchon, 2016). However, via miR-130a reduction, RA induces HOXA5 in breast cancer tissue (Yang, Miao, Mei, & Wu, 2013). RA also acts as a inducer for miR-10a, which counteracts the reduced miR-10a and RARβ in breast cancer cells (Khan et al., 2015). To add on, RA increases miR-210 and miR-23a/24–2 but decreases miR-17/92 and miR-424/450b in breast cancer cells. However, estrogen can counteract the effect of RA on expression of those four miRNAs (Saumet et al., 2012).

In a specific subgroup of HER2-positive breast cancer cells, SKBR3, RA and Lapatinib treatment regulates the expression of 174 miRNAs (Fisher et al., 2015). Together, RA-regulated miRNAs have a significant impact on growth or mobility of SKBR3 cells (Fisher et al., 2015).

4.6. Digestive system cancers

RARβ is an upstream regulator and downstream effector of miR-22. In other words, RARβ can transcriptionally induces miR-22, which in turns epigenetically regulate the expression and function of RARβ and another orphan receptor named NUR77. As a result, nuclear NUR77 exports to cytosol converting its oncogenic effect into apoptotic effect thereby killing colon cancer cells (Hu et al., 2019). RA by itself or in combination with synthetic and natural HDAC inhibitors including short-chain fatty acids can induce miR-22. Thus, in addition to RARβ-mediated transcription, epigenetic mechanism also regulates miR-22 expression. Additionally, it is interesting that miR-22 targets multiple protein deacetylases including HDAC1, HDAC4, as well as SIRT1 and has HDAC inhibitory effect used to fight for cancer. Thus, RA-induced miR-22 is a tumor suppressor for colon cancer (Hu et al., 2019). Furthermore, reduced miR-22 is found in many other types of cancers including liver, colon, etc., and is considered as a tumor suppressor (Yang, Hu, Liu, & Wan, 2015). In consistency with the role of miR-22 being a tumor suppressor, miR-22 has been characterized as a metabolic silencer (Hu et al., 2020).

In metastatic pancreatic adenocarcinoma cells, miR-10a is overexpressed and regulates the metastatic behavior by suppressing HOXB1 and HOXB3. As mentioned above, miR-10a is important for RA-mediated differentiation of neuronal cells. However, in pancreatic adenocarcinoma, RAR antagonists reduces miR-10a and has an anti-cancer effect (Weiss et al., 2009).

Reduced miR-452 promotes stem-like features and tumorigenesis in glioma as mentioned above (Liu et al., 2013). However, increased miR-452 significantly promotes hepatocellular carcinoma (HCC) cell proliferation in vitro and in vivo (Zheng et al., 2016). miR-452 is overexpressed in the chemo-resistant hepatospheres and human HCCs (Zheng et al., 2016). Thus, miR-452 over-expression predicts poor survival for liver cancer patients (Zheng et al., 2016). Moreover, RA combined with doxorubicin reduces miR-452 and inhibits HCC metastasis (Zheng et al., 2016). Furthermore, miR-452 silences the Sox7, which suppresses the Wnt/β-catenin signaling pathway (Chan, Mak, Leung, Chan, & Ngan, 2012; Zheng et al., 2016).

4.7. Other cancers

As a tumor suppressor, reduced RARβ can be an indicator for prognosis. In papillary thyroid carcinoma, reduced RARβ is associated with increased miR-146b-5p (Czajka et al., 2016). Overexpression of miR-146a-5p and miR-146b-5p results in reduced RARβ mRNA (Czajka et al., 2016). In contrast, toll-like receptor 3 (TLR3) activation induces RARβ re-expression and tumor inhibition, which is due to increased miR-29b, −29c, −148b, and −152 as well as re-expression of epigenetically silenced genes (Galli et al., 2013).

Another miRNA that targets RARβ is miR-29b. Tuberous sclerosis complex (TSC) is an incurable multisystem disease featured by mTORC1-hyperactive tumors. It has been found that by targeting RARβ, miR-29b has an oncogenic effect in TSC2-deficient cells. In addition, inhibition of miR-29b suppresses oncogenic property of TSC2-deficient tumors in vivo (Liu et al., 2019).

In addition to RARβ, miRNAs also affect the expression of other RA receptors. miR-27a overexpression, which silences RARα and RXRα, is found in aggressive rhabdomyosarcomas cells (Tombolan et al., 2015). Additionally, RA can enhance the binding of RARα to the miR-27a promoter, leading to the inactivation of miR-27a transcription, which increases glycogen synthase kinase-3β (GSK-3β) in laryngeal cancer cells. However, the mechanism by which RARα reduces miR-27a remains to be understood (Chen et al., 2017).

The effects of other retinoids in regulating miRNA have been studied. For example, the treatment effect of 9-cis RA, a ligand for RXR, is revealed in an adrenocortical xenograft mouse model. 9-cis RA together with mitotane reduce circulating hsa-miR-483–5p in the adrenocortical xenograft mouse model and can potentially be a predictor of treatment efficacy (Nagy et al., 2015). Additionally, tomato-derived bioactive antioxidants such as carotenoids and lycopene also inhibit tumor growth. In PC3 prostate cancer cells, lycopene increases let-7f-1 to silence the AKT2 and induce apoptosis (Li, Chen, Zhao, Hao, & An, 2016).

5. miRNAs that are implicated in other RA-regulated health issues

5.1. Liver diseases

Overexpression of miR-34a in human hepatoblastoma HepG2 cells reduces RXRα mRNA and protein. An inversely correlated expression pattern exists between miR-34a and RXRα protein in 14 liver specimens, with fibrotic livers having increased miR-34a but reduced RXRα. p53 can up-regulate miR-34a and promote liver fibrosis. Thus, by reducing RXRα, miR-34a has a role in liver fibrosis (Oda et al., 2014).

5.2. Atherosclerosis

miR-10a is a potential diagnostic molecule because reduced miR-10a in aortic endothelium and serum is linked with atherosclerosis (Lee et al., 2018). Moreover, RARα/RXRα-specific agonists induce miR-10a in vascular endothelial cells and inhibit atherosclerotic lesion formation. Thus, the RA-induced miR-10a can be a potential target for treating atherosclerosis (Lee et al., 2018).

5.3. Congenital diseases

Through hypermethylation, miR-124a is reduced and p38 is deactivated in RA-induced spina bifida fetuses compared with healthy rats. In addition, p38 deactivation is accompanied by increased apoptosis suggesting the role of miR-124a in RA-induced congenital defect (Qin et al., 2017). RA also reduces miR-9/9*, miR-124a, and miR-125b, all of which are implicated in the development of spina bifida in rat models (Zhao et al., 2008). The up-regulation of miR-9, miR-124a, and miR-138 as well as down-regulation of miR-134 are found in the amniotic fluid of RA-induced spinal bifida fetuses compared with that of control fetuses (Qin et al., 2016).

5.4. Aging

miRNAs that are implicated in stress-induced premature senescence have been identified in primary cultures of human diploid fibroblasts and human trabecular meshwork cells. Senescence is associated with reduced miR-15 and miR-106b as well as increased miR-182 and −183. In addition, miR-106b and miR-182 target the p21CDKN1A and the RARG, respectively, and are thereby implicated in senescence (Li, Luna, Qiu, Epstein, & Gonzalez, 2009).

5.5. Myopia

Mutation of the paired box gene 6 (PAX6) gene, which controls oculogenesis, is implicated in the development of myopia. RA induces miR-328, which targets the PAX6, in retinal pigment epithelial cells leading to increased retinal pigment epithelial cell proliferation and reduced scleral cell proliferation. Thus, the reduction of miR-328 contributes to the prevention or treatment of myopia (Chen et al., 2012).

5.6. Alzheimer’s disease

Overexpression of miR-138 is found in the N2a/APP cells expressing human amyloid precursor proteins (APP) 695 protein (APP695, APPwt) and HEK293/tau cells (human embryonic kidney 293 cells expressing human tau protein). In HEK293/tau cells, increased miR-138, which directly targets the RARα, activates GSK-3β, and enhances tau phosphorylation. In contrast, elevated RARα inhibits GSK-3β and reduces tau phosphorylation (Wang et al., 2015).

6. Conclusion

miRNA has a significant role in mediating the functions of RA. Among the above-mentioned miRNAs, there are a few such as let-7, miR-10, and miR-17 are implicated in multiple biological processes and disease models.

The let-7 family has a wide variety of implications. Increased Let-7g leads to the differentiated phenotype of Dicer-deficient mouse ESCs. Furthermore, the let-7 family has a variety of effects on neuronal lineage progression cells. It induces neuronal differentiation and is elevated in differentiated neuronal cultures. They can also act as tumor suppressors and lead to the differentiation of APL cells. Moreover, let-7f-1 induced by lycopene causes apoptosis.

The miR-10 family also has a wide variety of implications after RA induction. For example, reduced miR-10a is linked to atherosclerosis and can be a diagnostic tool. Furthermore, miR-10a promotes the differentiation of mouse embryonic stem cells into smooth muscle cells. miR-10a is also found in T cells and stabilizes iTregs that prevents their development into helper T cells. In addition, miR-10a level is low in breast cancer cells but is overexpressed in metastatic pancreatic adenocarcinoma cells.

miR-17 is generally decreased by RA. It is involved in the regulation of the MAPK signaling pathway, synaptic plasticity, and other markers of neuronal differentiation in neuroblastoma SH-SY5Y cells. It is also decreased in APL cell differentiation and in breast cancer cells. In addition, reduced levels of miR-17 also promotes the macrophage inflammatory responses such as infiltration, phagocytosis, and pro-inflammatory cytokine secretion. miR-17–92 also functions cooperatively with miR-106b-25 to regulate mice spermatogonia differentiation.

Since miRNA can target many genes and pathways, it would be challenging to use them for disease treatment and prevention. Additionally, certain miRNAs such as miR-452 has opposite effects based on the tumor types. Additional studies are required to dissect their functions and human relevance.

Funding

This study is supported by grants funded by National Institutes of Health U01CA179582 and R01CA222490.

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