JCB J Circ Biomark 2022; 11: 14-23ISSN 1849-4544 | DOI: 10.33393/jcb.2022.2356REVIEW Journal of Circulating Biomarkers - ISSN 1849-4544 - www.aboutscience.eu/jcb © 2022 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu Introduction Epigenetics is defined as hereditary changes in gene expression without altering the deoxyribonucleic acid (DNA) sequence (1). Methylation of cytosine in the DNA sequence and the biochemical changes of histones are two critical mechanisms in the epigenetics that play an important role in gene regulation, differentiation, and carcinogenicity (2-5). Another mechanism that affects epigenetics and the gene expression is microribonucleic acids (miRNAs). miRNAs are non-coding endogenous RNAs with a length of 20 to 25 nucleotides. These molecules can bind to untranslated 3′ regions (UTRs) and suppress the expression of messenger RNAs (mRNAs) at the posttranscriptional level by pairing a specific base sequence (6,7). miRNAs bind to their target mRNAs and regulate their stability and/or translation. If miRNAs bind completely to their target sequence on the The role of microRNAs in COVID-19 with a focus on miR-200c Hadi Sodagar1, Shahriar Alipour1,2, Sepideh Hassani1, Shiva Gholizadeh-Ghaleh Aziz1, Mohammad Hasan Khadem Ansari1, Rahim Asghari3,4 1Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia - Iran 2Student Research Committee, Urmia University of Medical Sciences, Urmia - Iran 3Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia - Iran 4 Hematology, Immune Cell Therapy and Stem Cells Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia - Iran ABSTRACT Objective: Epigenetics is a quickly spreading scientific field, and the study of epigenetic regulation in var- ious diseases such as infectious diseases is emerging. The microribonucleic acids (miRNAs) as one of the types of epigenetic processes bind to their target messenger RNAs (mRNAs) and regulate their stability and/ or translation. This study aims to evaluate non-coding RNAs (ncRNAs) with a focus on miR-200c in COVID-19. In this review, we first define the epigenetics and miRNAs, and then the role of miRNAs in diseases focus- ing on lung diseases is explained. Finally, in this study, we will investigate the role and position of miRNAs with a focus on miR-200c in viral and severe acute respiratory syndrome–related coronavirus (SARS-CoV2) infections. Methods: Systematic search of MEDLINE, PubMed, Web of Science, Embase, and Cochrane Library was conducted for all relative papers from 2000 to 2021 with the limitations of the English language. Finally, we selected 128 articles which fit the best to our objective of study, among which 5 articles focused on the impact of miR-200c. Results: Due to the therapeutic results of various drugs in different races and populations, epigenetic processes, especially miRNAs, are important. The overall results showed that different types of miRNAs can be effective on the process of various lung diseases through different target pathways and genes. It is likely that amplified lev- els of miR-200c may lead to decreased angiotensin-converting enzyme-2 (ACE2) expression, which in turn may increase the potential of infection, inflammation, and the complications of coronavirus disease. Conclusion: miR-200c and its correlation with ACE2 can be used as early prognostic and diagnostic markers. Keywords: Covid-19, Epigenetic, Lung diseases, miR-200c, miRNAs Received: November 5, 2021 Accepted: February 22, 2022 Published online: March 21, 2022 Corresponding author: Shahriar Alipour Department of Biochemistry, Faculty of Medicine Urmia University of Medical Sciences 11km SERO Road 0098 Urmia - Iran alipour.sh@umsu.ac.ir Shiva Gholizadeh-Ghaleh Aziz Department of Biochemistry, Faculty of Medicine Urmia University of Medical Sciences 11km SERO Road 0098 Urmia - Iran gholizadeh.sh@umsu.ac.ir https://doi.org/10.33393/jcb.2022.2356 https://creativecommons.org/licenses/by-nc/4.0/legalcode Sodagar et al J Circ Biomark 2022; 11: 15 © 2022 The Authors. Published by AboutScience - www.aboutscience.eu mRNA, they can lead to degradation; but in case of binding incorrectly, translational suppression of their target genes occurs by a mechanism that has not yet been fully understood (8). Each miRNA is predicted to have multiple gene targets and each mRNA may be regulated by more than one miRNA (9,10). The miRNAs play a vital role in many important biolog- ical processes, including cell proliferation (11), growth (12), differentiation (13), apoptosis (14), metabolism (15), aging (16), signal transduction (17), and viral infections (18). It is estimated that about one-third of genes and their pathways are regulated and controlled by miRNAs. Briefly, miRNAs have a remarkable effect on the genomic and epigenetic mechanisms (19,20). The role of miRNAs in diseases focusing on lung diseases The miRNAs involve in the development, progression, prognosis, diagnosis, and evaluation of therapeutic response in human diseases (21). In recent years, altered expression of the miRNAs has been identified in many human cancers (22), cardiac hypertrophy and failure (23), metabolic disorders (24), immune system–related diseases, and inflammation (9). Also, the miRNAs have been studied in lung homeosta- sis, functional development, and various pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and lung cancer (25) (Tab. I). In recent years, an increasing amount of research has shown the impact of miRNAs in the progress of pulmonary diseases (43). Our knowledge of the role of miRNAs in lung diseases has developed step by step. The role of miRNAs in the unique pulmonary cells is thought to be essential in understanding the mechanism of lung function and disease pathogenesis (25). More recently, many studies have begun to report the effects of miRNA transfer via extracellular vesi- cles. In lung diseases, this transfer was indicated to be facili- tated via the intercellular communication between many types of cells in the respiratory system including endothelial cells (44), bronchial epithelial cells (45), mesenchymal stem cells, and others (46). TABLE I - Relationship between miRNA types and their target genes in different lung diseases RefMeasurement typeSampleExpression in diseaseGene targetmiRNADisease (26,27)Quantitative PCRPBUpRUNX3miR-145 Asthma (49)qRT-PCRSerumUpIL-12miR-21 (50)qRT-PCRhBSMCsDownRhoAmiR-133a (28)RT-PCRBECUpTGFβR2mir-19a (48)RT-PCRMacrophages—monocytesUpIL-13Ra1miR-155 (29)qRT-PCRLung UpSMAD7miR-15b COPD (30)RT-PCR/Northern BlotPLFDownCOX-2miR-146a (31)RT-PCRLung DownBIMmiR-24-3p (32)High-throughput microarrayPBMCsUpNFKBIAmiR-93-5 (33)RT-PCR LungDownTOM1miR-126 CF (34)qRT-PCR Cell lineUpCFTRmiR-145 (61)Quantitative PCR Cell cultureDownSIN3AmiR-138 (35)RT-PCRBronchial tissuesUpANO1miR-9 (36)MicroarraysLung DownHMGA2let-7d IPF (37)miRNA array/Northern blottingLung UpSmad, Smad7miR-21 (38)miR ArrayHLTDownTGF-β1miR-200c (39)TaqMan miRNA assaySerumUpTGF-βmiR-199a-5p (40) Bioinformatics analysis and luciferase reporter assay LungDownSLC22A18miR-137 Lung cancer (41)qRT-PCR and Western blotTissuesDownTGFβR2mirRNA-34a (42)RT-PCRLung cancer tissueDownE2F3miR-449a (55)RT-PCRTissueDownZEB1miR-200 BEC = human bronchial epithelial cells; CF = cystic fibrosis; CFTR = Cystic Fibrosis Transmembrane Channel; COPD = chronic obstructive pulmonary disease; HLT = human lung tissue; IPF = idiopathic pulmonary fibrosis; miRNA = microribonucleic acid; PB = peripheral blood; PLF = primary lung fibroblast; qRT-PCR = quantitative reverse transcription polymerase chain reaction; PBMC = peripheral blood mononuclear cell; hBSMC = Human Bronchial Smooth Muscle Cells. COVID-19: role of mRNAs and miR-200c16 © 2022 The Authors. Journal of Circulating Biomarkers - ISSN 1849-4544 - www.aboutscience.eu/jcb The miRNAs in Asthma Asthma is a chronic inflammatory disease of the lungs that is often associated with clinical features such as airway hyperresponsiveness (AHR), airflow obstruction, excessive mucus secretion, and airway wall structural changes (remod- eling) (47). Interleukin (IL)-13 and transcription factor signal transducer-and-activation-of-transcription-6 (STAT6)-operated path ways have been shown to play a significant role in regu- lating the prominent asthma features, for example, AHR and remodeling. miR-155 has been shown to be upregulated in order to target directly the transcription of the IL-13 recep- tor a1 (IL13Ra1) in human macrophages, reducing the lev- els of IL13Ra1 protein and decreasing the levels of activated STAT6, which is vital in regulating the IL-13 signaling pathway (48). Inhibition of miR-21 leads to a decrease in Th2 cytokine levels (IL-4, IL-5, and IL-13), the number of inflammatory air- way leukocytes and AHR (49). Downregulation of miR-133a was followed by an increased expression of RhoA and subse- quently increased bronchial hyperactivity in a murine model of asthma (50). Elevated expression of the miR-155 has also been indicated in murine models of asthma. Additionally, by using antagomir against miR-145, the mucus secretion, Th2 cytokine production, and eosinophil infiltration in the air- ways decreased (51). The miRNAs in lung cancer Dysfunction of miRNAs is often identified in malignan- cies, including lung tumor. Lung cancer is the leading cause of cancer-related mortality worldwide and to date the roles of miRNAs in lung cancer have been specified and reviewed widely along with the other diseases. Histologically, lung can- cer can be mostly divided into small cell (SCLC) and non–small cell lung cancer (NSCLC). The latter is more common and is subclassified into squamous, adenocarcinoma, and large-cell carcinoma (52). Recent sequencing studies have exposed a very large number of targets for each single miRNA. By regulating the posttranscriptional gene expression, miRNAs strongly involved in wide-ranging pathways with the main effect are on the progressive and carcinogenesis routes (53,54). Concisely, various miRNAs that are recognized as either oncogenes or tumor suppressors in lung cancer are also involved in the immune system response, for instance, the miR-200 family. The low expression of the miR-200 fam- ily members in human early-stage lung adenocarcinomas has been correlated with upregulation of PD-L1 (55) and CD8+ T-cell immunosuppression and metastasis, which resulted in the reduction of tumor load. This finding greatly supported the role of miR-200 as a tumor suppressor. The miRNAs in COPD COPD is an inflammatory progressive lung disease that is prompted by chronic inflammation exposure of the airways to stimuli including cigarette smoking and other noxious gases. An increasing number of studies have demonstrated that injured cells such as endothelial and epithelial cells participate seriously in the pathogenesis of COPD (56). The exposure of the respiratory epithelial cells to the harmful agents like cigarette smoke leads to the release of proinflam- matory and inflammatory cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α (57,58). The miRNAs and CF In the Caucasian community, CF is the most frequent deadly hereditary disease. It is caused by a recessive mutation in the CFTR (Cystic Fibrosis Transmembrane Channel) gene, which codes for a chloride channel (59). miRNAs can target CFTR directly or indirectly for regulating CF. Several miRNAs can complementarily and directly regulate CFTR expression such as miR-145 (via SMAD3 and TGF-β), miR-223 (via CFTR mRNA), miR-9 (via Anoctamin 1), and miR-494 (via Solute Carrier family 12Member 2 (SLC12A2)), alone or together. However, miR-509-3p and miR-494 downregulate CFTR expression (60). Some miRNAs like miR-138 can also repress the biosynthesis intermediary actors, such as the transcription factor SIN3A (SIN3 transcription regulator family member A) and CFTR (61). The miRNAs and infections Recent advances in molecular mechanisms point to the importance of miRNAs in the lung and respiratory infections. Acute viral respiratory infections (AVRIs) are the most com- mon causes of acute respiratory symptoms (62). Changes in the regulation of miRNA expression in the epithelial cells of human rhinovirus (hRV), influenza (IV), human metapneu- movirus, human coronavirus, and respiratory syncytial virus infections are associated with the pathogenesis of acute respiratory diseases (63). For example, the expression of host miRNAs changes in response to IV stimulation. These miRNAs directly or indirectly target viral and host genes to regulate virus replication, stimulate or suppress innate immune responses and cell apoptosis during the viral infec- tion (64,65). IV increases the expression of miR-4276 by upregulating two proteins involved in the apoptotic pathway, Cas9 and Cocx6c (74), and eventually leads to increased virus replication and apoptosis. Furthermore, a number of specific cellular miRNAs in IV-infected cells including miR-323, mir- 491, and miR-654 target the protected region of viral PB1 gene to prevent the virus from replicating in MDCK cells (76). Another mechanism in IV infection is the altered expres- sion of cellular miRNAs and their effect on important signal- ing pathways associated with the immune system (66). In hRV infections, miRNAs result in antiviral responses by modulating the immune response (miR-128 and miR-155) as well as con- trolling virus entry into the infected lung cells (miR-23b) (67). RSV causes viral respiratory disease in infants and young children (68), modulating the expression of host cell miRNAs for antiviral responses and virus replication similar to the miRNAs mentioned above (69,70). For instance, miR-125a regulates nuclear factor kappa B (NF-κB) signaling pathway by suppressing A20 inhibitor protein (CCL5) as an important cytokine in both innate and compatible immune systems (71). Coronaviruses cause a wide range of respiratory infections, from mild upper respiratory tract infections to severe lower respiratory tract infections (72). Table II shows the four major Sodagar et al J Circ Biomark 2022; 11: 17 © 2022 The Authors. Published by AboutScience - www.aboutscience.eu TABLE II - Relationship between different types of miRNAs and their target genes in well-known viral lung infections RefPathwaysEffects on gene regulation Gene targetmiRNAViral disease (74)–  Inhibits COX6C and caspase-9 and promoting viral replication –  Up–  COX6C–  miRNA-4276 Influenza virus (75)–  Inhibits replication of virus –  Up–  PB1–  miR-323, miR-491 (76)–  Reduces virus replication by degrading M1 mRNA –  Up–  M1–  let-7c (77)–  Negatively regulates innate immune and inflammatory responses –  Up–  TRAF6–  miR-146a-5 (78)–  Regulates virus entry –  Down–  AP1G1–  miR-576-3p (79)–  Suppresses IAV replication –  Down–  HDAC8–  miR-21-3p (64)–  Regulates antiviral response –  Up–  MAPK3, IRAK1 –  miR-132, miR-200c (80)–  Regulates the immune response against RV-1B and inhibits virus replication –  Up–  SMAD2, EGFR –  miR-128 , miR-155 Rhinoviruses (81)–  Prevents viral infection by decreasing the VLDLR –  Up–  VLDLR–  miR-23b (82)–  Antiviral host response –  UpCCL7, SOCS3 let-7f RSV (83-85)–  Induces miRNAs to involve in the immune response pathways such as NF-kB and type I IFNs –  Up–  IL-13, TLR4, RUNX2  miR-30, let-7i (86)–  Promotes viral replication –  Down–  NGF, TrkA miR-221 (87)–  Inhibits NF-κB signaling pathway and results in reducing macrophage activation –  Down–  TNFAIP3 miR-125a (88)N protein of virus binds to miR-9 and modulates NF-kB expression Up–  NF-kBmiR-9OC43 Coronavirus (89,90)–  Suppresses viral replication that may aid evasion of immune surveillance until successful infection of other cells Up–  Virulent proteins, including N, S, M, and E miR-17, miR-574-5p, miR-214SARS (91)–  miRNA-mRNA network significantly impacts MERS-CoV replication Up–  MAP3K9, MYO15B, SPOCK1   miR-16-1-3p, miR-26a-1- 3p, miR-425-5p, miR-1275, miR-2277-5p , miR-500b-5p, miR627-5p, miR-1257, miR-1275 MERS (92)–  These miRNAs may downregulate viral gene expression resulting in the inhibition of viral replication Up–  Viral mRNAmiR628-5p, miR-18a-3p, hsa-miR332-3p MERS (93)–  Acts as a negative regulator of NF-κB as the transcription factor of the IL-6 gene DownIL-6 miR-146a-5pSARS- CoV2 –  Overexpression of miR-200c induces downregulation of ACE2 in human cells UpACE2 miR-200c (94)–  Targets SARS-CoV2 genome UpSARS-CoV2 ORF1a/b  miR-1202 (95)–  Expression of let-7d-5p negatively correlates with TMPRSS2 expression 91 Up–  TMPRSS2let-7d-5p IL = interleukin; MERS = Middle East respiratory syndrome; miRNA = microribonucleic acid; NF-κB = nuclear factor kappa B; RSV = respiratory syncytial virus; SARS-CoV = severe acute respiratory syndrome–related coronavirus; IAV = Influenza A viruses. COVID-19: role of mRNAs and miR-200c18 © 2022 The Authors. Journal of Circulating Biomarkers - ISSN 1849-4544 - www.aboutscience.eu/jcb categories of the pulmonary virus families and some of the most important miRNAs that change the expression of the genes involved in infections with these viruses. Severe acute respiratory syndrome coronaviruses (SARS-CoV) use host cell miRNAs to escape removal by the immune system (89). In Middle East respiratory syndrome coronavirus (MERS- CoV) infection, cellular miRNAs act as an antiviral thera- peutic agent (92). The functional mechanisms of miRNAs in SARS-CoV2 as the causative agent of COVID-19 are diverse. For example, increased miR-200c expression in the disease downregulates the expression of angiotensin-converting enzyme (ACE2) protein that is the receptor essential for the virus entry into the cell (73). Association of miR-200c with the genes involved in inflammation (ACE2, IL-6) miR-200c-3p is a member of the miR-200 family with two clusters miR-200a/b/429 and miR-200c/141. The miR- 200c-3p is one of the most important miRNAs of the second cluster. Studies on the miR-200 family have shown that it has a variety of roles in cancer progression, drug resistance, and oxidative stress (96,97). The results of various studies have revealed the crucial role of the miR-200c epithelial-mesen- chymal transmission, proliferation, metastasis, apoptosis, autophagy, and therapeutic resistance in several types of cancer (98). The miR-200c is also measured as a biomarker to predict disease progression, diagnosis, and response to therapy in several cancers, both in tissues and in body fluids (blood, urine) (96). Studies using miRNAs can contribute not only to the understanding of virus-host interactions but also to the strati- fication of the different severities of COVID-19. In this sense, miR-200c-3p, which has been associated with viral infec- tions, including influenza A, offers itself as a candidate for the study of COVID-19. The analysis of its expression in groups of patients presenting different levels of disease aggressiveness could contribute to a better screening of patients affected by SARS-CoV2. Thus, in Pimenta’s study, which aimed to analyze the expression of miR-200c-3p in saliva samples from patients with COVID-19, the results showed that the expression pat- tern of miR-200c-3p increased with disease severity (99). Furthermore, the significant impact of miR-200c-3p in acute respiratory distress syndrome (ARDS) was discov- ered, which proposes it as a potential factor in SARS-COV-2 research and is considered as a potential diagnostic agent for SARS-COV-2 studies (100). In a study of the H5N1 avian influ- enza virus (AIV) ACE, serum levels of miRNA-200c-3p were found to increase in the virus causing acute pulmonary injury and ARDS. This miRNA binds to the 3′-UTR locus of the ACE2 gene, and inhibits the expression of this protein and thus exacerbates the disease (100-102). The ACE2 gene was first identified from complementary DNA in the left ventricle of the human heart (102). ACE2 inac- tivates angiotensin II (Ang II) by cleavage and produces Ang 1-7 (103). Ang II binds to type 1 and type 2 Ang II receptors with high affinity and is involved in regulating blood pressure, body fluid balance, inflammation, cell proliferation, hypertrophy, and fibrosis (104-106). ACE2 has been shown to neutralize the development of severe ARDS caused by AIV, coronavirus, and sepsis in mice (106). ACE2 has also been reported as a receptor for the SARS-CoV2 virus to enter the pneumocytes (107). The role of miR-200c in lung inflammation and lung diseases MiR-200c, alongside with miR-141, is placed in the intra- genic zone of chromosome 12. MiR-200c family has beneficial effects on preventing drug resistance, cancer development, and oxidative stress. It consists of two clusters: (1) miR-200c/141 cluster including miR-141-3p and miR-141-5p, miR-200c-3p, miR-200c-5p on chromosome 12p13.31; (2) miR-200a/ b/429 cluster including miR-200a-3p, miR-200a-5p, miR- 200b-3p, miR-200b-5p, and miR-429 on chromosome 1p36.33 (108). miR-200, like ACE2, is greatly expressed in the epithelial cells of the pneumocytes, mainly in type II alveolar epithelial cells. The expression of miR-200 has a crucial role in the dif- ferentiation of type II alveolar epithelial cells in fetal lungs, which are important components of the renin-angiotensin system signaling pathway all over the body. miR-200 displays several important effects in the body such as anti-remodel- ing, anti-inflammatory, and anti-proliferative through reduc- tion of angiotensin II levels (Fig. 1) (109). Remarkable points in this issue are about controlling COVID-19 patients’ mor- tality rates and disease severity, by upregulating ACE2 levels with using angiotensin receptor blockers or ACE2 blockers (110). miR-200 is the exact and direct target of ACE2 at 3′-UTR of ACE2 mRNA which by binding to its locus results in the depression of ACE2 expression as a receptor responsible for ARDS incidence. Normally, ACE2 catalyzes the conversion of AgII to Ag1-7. Later, Ag1-7 binds to mitochondrial assembly (MAS) receptors resulting in Ag1-7 protective effects includ- ing anti-proliferation, anti-necrotic and anti-hypertrophic as well as vasodilation and declining of proinflammatory cyto- kine secretion. SARS-CoV2 inhibits this pathway and worsens AgII adverse effects on lung tissue during the acute phase of the disease. It was reported that SARS-CoV2 induces the secretion of IL-6, TNF-α, IL-1β (102,111-113). Activation of NF-κB pathway, an important factor in ARDS pathogenesis, is one of the noticeable pathways leading to the upregula- tion of miR-200c-3p. Increased expression of miR-200c-3p occurred when the ACE2 expression decreased (100) (Fig. 1). These mechanisms include increased mir-200c expres- sion, inhibition of ACE2 expression, by affecting ACE2 protein outside the cell, and by inhibition of other anti-inflammatory functions, all of which are shown in the figure. (1) increased miR-200c expression that SARs-CoV-2 inhibit ACE2 indirectly by regulating miR-200c and directly inhibiting ACE2 expres- sion, (2) by affecting the ACE2 gene, (3) ACE2 protein outside the cell, and (4) by inhibiting other anti-inflammatory func- tions, all of which are shown in the figure. In addition, miR- 200c can also reduce ace2 expression, thereby reducing ACE2 expression and reducing its function. According to research results, the reduction in disease severity in COVID-19 patients associates with the correlation between low expression of ACE2 and high levels of miR-200c-3p in the lungs and the upper respiratory tract (114,115). Sodagar et al J Circ Biomark 2022; 11: 19 © 2022 The Authors. Published by AboutScience - www.aboutscience.eu Recent studies about the entrance of SARS-CoV-2 to the host cells imply that some miRNAs can actually control the expression of ACE2 and TMPRSS2, which are potentially of high effect in SARS-COV-2 pathogenesis (116). Several pathways have been studied about the effect of epigenetics on the regulation of ACE2/TMPRSS2 expression levels in respiratory diseases. The epigenetic repression of miRNA transcription can control their regulatory regions. For instance, Lysine-specific demethylase 5B (JARID1B, encoded by the KDM5B gene) was displayed to suppress the tran- scription of miR-200 family including miR-141, miR-200a, miR-200b, miR-200c, and miR-429. Hsa-miR-125a/hsa-let-7e miRNAs inhibit the transcription of miR-200 family through stimulating H3K4me3 histone, which demethylases the miRNAs of this family. Therefore, hsa-miR-125a-5p via binding to miR-200 family pursues 3′-UTR of ACE2 mRNA and results in the enhancement of ACE2 gene expression while 3′-UTR of the TMPRSS2 is targeted by hsa-let-7e-5p. Concludingly, JARID1B epigenetic activity doesn’t directly regulate the expression of ACE2 and TMPRSS2 (116). Scientists have investigated if promoting H3K4me3 demethylation is caused by repression of the transcription of the let-7e and miR-125a via JARID1B gene (117); for example, the upregulation of JARID1B in lung cancer cell line A549 concluded threefold depression of miR-200a and miR-200c expression, while JARID1B knockdown enhanced 1.5-fold their conserved and stable levels (118). The experimental data show the presence of control- ling network containing miR-125a/let-7e/miR-200 families, ACE2/TMPRSS2 as well as histone demethylase JARID1B, and further point a new way for signaling pathway for ACE2 expression. In one report, the single-cell RNA sequencing data analysis sharply indicated that in the majority of human cells ACE2 and TMPRSS2 are not expressed without JARID1B. So, for better understanding, the viral infection pathogenesis needs to be investigated in the regulatory network related to the expression of JARID1B, ACE2, and TMPRSS2 in human respiratory epithelial cells (116). According to cellular ontologies research on 24 miRNAs, for evaluating the miRNAs targeting SARS-CoV-2 host cell receptor ACE2, it was revealed that miR-429, miR-200a-3p, miR-210-3p, miR-200b-3p, and miR-200c-3p were highly expressed in the respiratory epithelial cells and miR-200c-3p exists abundantly in the cells including endo-epithelial cell, epithelial cells, respiratory epithelial cells, leukocytes, hema- topoietic cells, and myeloid leukocytes. Also, miR-200b Fig. 1 - MiR-200c and ACE2 mechanism of function in the pathogenesis of COVID-19. SARS-CoV2 induces inflam- mation and severe ARDS through four mechanisms: (1) virus indirectly leads to ACE2 downregulation by enhan- cing miR-200c expression. (2) Virus directly inhibits ACE2 gene expression. (3) SARS- CoV2 inhibits binding of ACE2 protein to its receptor on the lung cells. (4) SARS-CoV2 inhi- bits the anti-inflammatory ef- fects of ACE2. ACE2 = angio- tensin-converting enzyme-2; ARDS = acute respiratory di- stress syndrome; COVID = co- ronavirus; SARS-CoV = severe acute respiratory syndrome– related coronavirus. COVID-19: role of mRNAs and miR-200c20 © 2022 The Authors. Journal of Circulating Biomarkers - ISSN 1849-4544 - www.aboutscience.eu/jcb and miR-200c were discovered to be extremely conserved (119). In clinical trials, miR-200 and its correlation with ACE2 can be used as early prognostic and diagnostic markers. Its loca- tion on the upstream of ARDS signaling pathways may reduce the morbidity and mortality rates of COVID-19 via epigenetic procedures, which can be so beneficial for human survival. Conclusion At present, there is no exact treatment for COVID-19. Due to the importance of miRNAs in pulmonary diseases, mainly the infectious viral diseases as well as SARS-COV-2, they can be potential candidates of targeted therapy in SARS-COV-2 in order to reduce the morbidity and mortality rates of this dis- ease as miR-200c and its correlation with ACE2 can be used as early prognostic and diagnostic markers. However, fur- ther research must be carried out to reveal the exact effect of miR-200c in the pathogenesis of COVID-19 in order to be used clinically. Authors’ contributions HS was responsible for the largest share in writing the article. SA and SG-GA conceptualized and wrote the article and article design. However, SA share has been higher. SA contributed in review and editing of final submitted version. MHKA and RA contributed in Methodology, Data validation and Writing original draft of this article. 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