MicroRNA-141-3p and microRNA-200a-3p regulate ?-melanocyte stimulating hormone-stimulated melanogenesis by directly targeting microphthalmia-associated transcription factor.
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PROVIDER: S-EPMC7005774 | BioStudies |
REPOSITORIES: biostudies
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Project description:BACKGROUND:Melanocytes are derived from neural crest stem cells in the embryonic stage. In mature melanocytes, a series of complex enzyme-catalyzed reactions leads to the production of melanins, which determine the hair and skin colors of animals. The process of melanogenesis is complex and can be regulated by mRNA, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) genes. MiRNAs are a type of endogenous noncoding RNA approximately 22 nt in size that predominantly regulate gene expression by inhibiting translation. miR-380-3p is a candidate miRNA potentially related to melanogenesis. To better understand the mechanism of miR-380-3p melanogenesis regulation, plasmids to overexpress or knockdown miR-380-3p were transfected into alpaca melanocytes, and their effects on melanogenesis were evaluated. RESULTS:In situ hybridization identified a positive miR-380-3p signal in alpaca melanocyte cytoplasm. Luciferase activity assays confirmed that SOX6 is targeted by miR-380-3p. miR-380-3p overexpression and knockdown in alpaca melanocytes respectively downregulated and upregulated SOX6 expression at the mRNA and protein levels. Additionally, miR-380-3p overexpression and knockdown, respectively, in alpaca melanocytes decreased and increased the mRNA levels of melanin transfer-related genes, including microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosine-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). In contrast, miR-380-3p overexpression and knockdown respectively increased and decreased the mRNA levels of β-catenin. Additionally, the effect of miR-380-3p on melanogenesis was assessed by Masson-Fontana melanin staining. CONCLUSIONS:The results demonstrated that miR-380-3p targeted SOX6 to regulate melanogenesis by influencing β-catenin and MITF transcription and translation, which reduced the expression of downstream genes, including TYR, TYRP1, and DCT. These results provide insights into the mechanisms through which miR-380-3p controls melanogenesis.
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Project description:The present study aimed to examine the potential inhibitory activity of oleoylethanolamide (OEA) on ?-melanocyte stimulating hormone (?-MSH)-stimulated melanogenesis and the molecular mechanism(s) involved in the process in B16 mouse melanoma cells. Our data demonstrated that OEA markedly inhibited melanin synthesis and tyrosinase activity in ?-MSH-stimulated B16 cells. In addition, the expression of melanogenesis-related proteins, such as melanocortin-1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and tyrosinase, was suppressed in a concentration-dependent manner by OEA. In addition, OEA may suppress melanogenesis through a peroxisome proliferator-activated receptor ? (PPAR?)-independent pathway. Moreover, OEA activated ERK, Akt, p38 pathways and inhibits CREB pathway in ?-MSH-stimulated B16 cells. The specific ERK inhibitor PD98059 partly blocked OEA-inhibited melanin synthesis and tyrosinase activity and partly abrogated the OEA-suppressed expression of melanogenic proteins. Furthermore, OEA presented remarkable inhibition on the body pigmentation in the zebrafish model system. Our findings demonstrated that OEA is an effective inhibitor of hyperpigmentation through activation of ERK, Akt and p38 pathways, inhibition of the CREB pathway, and subsequent down-regulation of MITF, TRP-1 and tyrosinase production.
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Project description:The individual parts of Morus alba L. including root bark, branches, leaves, and fruits are used as a cosmetic ingredient in many Asian countries. This study identified several anti-melanogenesis constituents in a 70% ethanol extract of M. alba leaves. The ethyl acetate fraction of the initial ethanol extract decreased the activity of tyrosinase, a key enzyme in the synthetic pathway of melanin. Twelve compounds were isolated from this fraction and their structures were identified based on spectroscopic spectra. Then, the authors investigated the anti-melanogenesis effects of the isolated compounds in B16-F10 mouse melanoma cells. Compounds 3 and 8 significantly inhibited not only melanin production but also intracellular tyrosinase activity in alpha-melanocyte-stimulating-hormone (?-MSH)-induced B16-F10 cells in a dose-dependent manner. These same compounds also inhibited melanogenesis-related protein expression such as microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-1 (TRP-1). Compound 3 modulated the cAMP-responsive element-binding protein (CREB) and p38 signaling pathways in ?-MSH-activated B16-F10 melanoma cells, which resulted in the anti-melanogenesis effects. These results suggest that compound 3, isolated from M. alba leaves, could be used to inhibit melanin production via the regulation of melanogenesis-related protein expression.
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Project description:Endometriosis is a common and benign gynecological disorder but exhibits malignant features. However, the underlying pathogenesis and pathophysiology of endometriosis remain unclear. Circular RNAs have been demonstrated to participate in the occurrence and progression of multiple diseases. This study was aimed to explore the roles of circATRNL1 in endometriosis in vitro. Based on the results of reverse transcription-quantitative polymerase chain reaction analysis, we found significant upregulation of circATRNL1 and Yes-associated protein 1 (YAP1), while downregulation of miR-141-3p and miR-200a-3p in ectopic tissues compared to eutopic tissues. The immunohistochemistry and western blot analysis showed differentially expressed epithelial-mesenchymal transition (EMT) markers between EuEM and EcEM tissues. The in vitro assays indicated that overexpression of circATRNL1 could promote the proliferation, migration, and invasion of Ishikawa cells, and induce EMT process, while circATRNL1 silencing showed the opposite effect. The mechanical investigation indicated that circATRNL1 upregulated YAP1 by sponging miR-141-3p and miR-200a-3p. Gain-of-function assays validated the inhibitory function of miR-141-3p and miR-200a-3p in endometriosis. The results of rescue assays confirmed the function of circATRNL1-miR-141-3p/miR-200a-3p-YAP1 axis on Ishikawa cells. Our findings demonstrate that abnormal upregulation of circATRNL1 regulates cell proliferation and motility and promotes EMT process via the miR-141-3p/miR-200a-3p-YAP1 axis in vitro, which could contribute to the progression of endometriosis.
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Project description:The synthesis of melanin pigments, or melanogenesis, is regulated by the balance of a variety of signal transduction pathways. Among these pathways, p38 MAPK signaling was found to be involved in stress-induced melanogenesis and to be activated by alpha-melanocyte-stimulating hormone (alpha-MSH) and ultraviolet irradiation. Previous studies have shown that alpha-MSH-stimulated melanogenesis can be inhibited by blocking p38 MAPK activity with SB203580, a pyridinyl imidazole compound. Consistent with this, we observed that pyridinyl imidazoles (SB203580 and SB202190) inhibited both basal and alpha-MSH-induced melanogenesis in B16 melanoma cells. However, SB202474, which has no ability to inhibit p38 MAPK activity and is usually used as a negative control compound in p38 MAPK studies, also suppressed melanin synthesis induction. Furthermore, the independence of the p38 kinase pathway from the repression of melanogenesis by pyridinyl imidazole compounds was also confirmed by small interfering RNA experiments. Interfering with p38 MAPK expression surprisingly stimulated melanogenesis and tyrosinase family protein expression. Although the molecular mechanism(s) by which p38 promotes the degradation of melanogenic enzymes remain to be determined, the involvement of the ubiquitin-proteasome pathway was demonstrated by co-treatment with the proteasome-specific inhibitor MG132 and the relative decrease in the ubiquitination of tyrosinase in cells transfected with p38-specific small interfering RNA.
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Project description:Dendropanax morbiferus H. Lév has been reported to have some pharmacologic activities and also interested in functional cosmetics. We found that the water extract of D. morbiferus leaves significantly inhibited tyrosinase activity and melanin formation in ?-melanocyte stimulating hormone (MSH)-induced B16-F10 cells. D. morbiferus reduced melanogenesis-related protein levels, such as microphthalmia-associated transcription factor (MITF), TRP-1, and TRP-2, without any cytotoxicity. Two active ingredients of D. morbiferus, (10E)-9,16-dihydroxyoctadeca-10,17-dien-12,14-diynoate (DMW-1) and (10E)-(-)-10,17-octadecadiene-12,14-diyne-1,9,16-triol (DMW-2) were identified by testing the anti-melanogenic effects and then by liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. DMW-1 and DMW-2 significantly inhibited melanogenesis by the suppression of protein kinase A (PKA)/cyclic AMP (cAMP)-responsive binding protein (CREB) and p38 MAPK phosphorylation. DMW-1 showed a better inhibitory effect than DMW-2 in ?-MSH-induced B16-F10 cells. D. morbiferus and its active component DMW-1 inhibited melanogenesis through the downregulation of cAMP, p-PKA/CREB, p-p38, MITF, TRP-1, TRP-2, and tyrosinase. These results indicate that D. morbiferus and DMW-1 may be useful ingredients for cosmetics and therapeutic agents for skin hyperpigmentation disorders.
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Project description:Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 1A expression by microRNAs (miRNAs) may be an important mechanism underlying interindividual variability in drug glucuronidation. Furthermore, the UGT1A 3'-UTR shared by all UGT1A enzymes is polymorphic, containing three linked SNPs (rs10929303, rs1042640, and rs8330) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT1A expression through binding to the reference and/or common variant UGT1A 3'-UTR. Luciferase reporter plasmids containing either the reference or variant UGT1A 3'-UTR were screened against a 2048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Four novel miRNAs (miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p) were identified that repressed both reference and variant UGT1A 3'-UTR, while two other miRNAs selectively repressed the reference (miR-1286) or variant (miR-21-3p) 3'-UTR. Deletion and mutagenesis studies confirmed the binding site location for each miRNA. rs8330 disrupted miR-1286 binding to the reference UGT1A 3'-UTR, while rs10929303 enhanced miR-21-3p binding to the variant 3'-UTR. Transfection of miR-21-3p, miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p mimics into LS180 human intestinal cells showed repression of UGT1A1 and UGT1A6 mediated glucuronidation and mRNA without affecting UGT2B7 activity or mRNA. Furthermore, transfection of miR-21-3p, miR-141-3p, and miR-200a-3p into primary human hepatocytes, repressed UGT1A1 activity and mRNA without affecting CYP3A activity. Finally, miR-21-3p and miR-200a-3p expression were negatively correlated with UGT1A6 activity and mRNA in human liver samples. Thus, UGT1A is regulated by multiple miRNAs with some showing allele-dependent effects.
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Project description:MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a-3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post-transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced ?-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression.
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Project description:Reliable measurement of the amount of melanin produced by melanocytes is essential to study various skin disorders and to evaluate the efficacy of candidate reagents for such disorders or for whitening purposes. Conventional melanin quantification methods are based on absorption spectroscopy, which measures the melanin from lysed cells grown on two-dimensional (2D) surfaces. The 2D culture environment is intrinsically different from in vivo systems though, and therefore cells often lose their original phenotypes. Melanocytes in particular lose their ability to synthesize melanin, thereby requiring melanogenesis stimulators such as alpha-melanocyte stimulating hormone (?-MSH) to promote melanin synthesis. In this study, we compared melanin synthesis in B16 murine melanoma cells grown in 2D and three-dimensional culture environments. B16 cells instantly formed an aggregate in a hanging-drop culture, and synthesized melanin efficiently without treatment of ?-MSH. We were able to measure the melanin secreted from a single melanocyte aggregate, indicating that our method enables non-invasive long-term monitoring of melanin synthesis and secretion in a high-throughput format. We successfully tested the developed platform by quantifying the depigmenting effects of arbutin and kojic acid.
2019-01-01 | S-EPMC6349835 | BioStudies
Project description:Acquisition of resistance to anti-cancer drugs is a significant obstacle to effective cancer treatment. Although several efforts have been made to overcome drug resistance in cancer cells, the detailed mechanisms have not been fully elucidated. Here, we investigated whether microRNAs (miRNAs) function as pivotal regulators in the acquisition of anti-cancer drug resistance to 5-fluorouracil (5-FU). A survey using a lentivirus library containing 572 precursor miRNAs revealed that five miRNAs promoted cell survival after 5-FU treatment in human hepatocellular carcinoma Hep3B cells. Among the five different clones, the clone expressing miR-200a-3p (Hep3B-miR-200a-3p) was further characterized as a 5-FU-resistant cell line. The cell viability and growth rate of Hep3B-miR-200a-3p cells were higher than those of control cells after 5-FU treatment. Ectopic expression of a miR-200a-3p mimic increased, while inhibition of miR-200a-3p downregulated, cell viability in response to 5-FU, doxorubicin, and CDDP (cisplatin). We also showed that dual-specificity phosphatase 6 (DUSP6) is a novel target of miR-200a-3p and regulates resistance to 5-FU. Ectopic expression of DUSP6 mitigated the pro-survival effects of miR-200a-3p. Taken together, these results lead us to propose that miR-200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.
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