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1.
Medicine (Baltimore) ; 99(7): e18897, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049790

RESUMO

This study aimed to investigate the correlation of microRNA (miR)-206, vascular endothelial growth factor (VEGF) and miR-206/VEGF axis at different gestational ages with fetal growth retardation (FGR) risk in pregnancies.Eight hundred twenty pregnancies were consecutively recruited and their plasma samples were collected at early pregnancy (gestational age ≤ 13 weeks), middle pregnancy (gestational age: 14-27 weeks) and late pregnancy (gestational age ≥ 28 weeks), respectively. miR-206 expression and VEGF level in plasma were detected by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay respectively. FGR was diagnosed based on the actual birth weight of fetus.miR-206 expression was negatively correlated with VEGF expression at early pregnancy, middle pregnancy and late pregnancy. Besides, miR-206 expression and miR-206/VEGF axis were elevated, but VEGF expression was decreased along with the increased gestational age. There were 74 FGR pregnancies and 746 non-FGR pregnancies. And both miR-206 expression and miR-206/VEGF axis were increased, but VEGF expression was reduced in FGR group compared to non-FGR group at early pregnancy, middle pregnancy and late pregnancy. Additionally, miR-206, VEGF and miR-206/VEGF axis at middle pregnancy and late pregnancy all showed good predictive values for FGR risk, and these indexes at late pregnancy exhibited the numerically highest predictive value for FGR risk. Furthermore, compared to miR-206 or VEGF alone, miR-206/VEGF axis presented with numerically higher predictive value for FGR risk.miR-206 predicts raised FGR risk through the interaction with VEGF in pregnancies, and it may serve as a novel biomarker for FGR prevention.


Assuntos
Retardo do Crescimento Fetal/genética , MicroRNAs/genética , Fator A de Crescimento do Endotélio Vascular/genética , Regiões 3' não Traduzidas , Adulto , Área Sob a Curva , Feminino , Retardo do Crescimento Fetal/metabolismo , Predisposição Genética para Doença , Idade Gestacional , Humanos , MicroRNAs/metabolismo , Gravidez , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
2.
Medicine (Baltimore) ; 99(3): e18740, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011454

RESUMO

To investigate the interaction between the single nucleotide polymorphism of the 3' untranslated region (3'UTR) of the pentraxin 3 (PTX3) gene, as well as environmental factors and the preeclampsia risk in a Chinese Han population.Sanger sequencing was used to analyze rs5853783 and rs73158510 loci of the PTX3 gene 3'UTR from 235 patients with preeclampsia and 235 control subjects. The plasma PTX3 protein level was measured by enzyme-linked immunosorbent assay (ELISA).The risk of preeclampsia in the PTX3 gene rs5853783 locus D allele carriers was 0.72 times higher than that of the I allele carriers (95% CI: 0.60-0.84, P < .001). The risk of preeclampsia in the PTX3 gene rs73158510 locus A allele carriers was 1.36 times higher than in the G allele carriers (95% CI: 1.16-1.55, P < .001). The area under the ROC curve (AUC) for the diagnosis of preeclampsia by plasma PTX3 protein levels was 0.906 (P < .001). The PTX3 gene rs5853783 and rs73158510 single nucleotide polymorphisms (SNPs) were associated with plasma PTX3 protein levels. The AUC of plasma PTX3 protein level diagnosis of preeclampsia in PTX3 gene rs5853783 locus II genotype subjects was up to 0.9371, followed by the ID genotype (AUC = 0.8586); the DD genotype was the lowest (AUC = 0.8154). The AUC of plasma PTX3 protein level diagnosis of preeclampsia in rs73158510 locus GG genotype subjects was 0.9102, GA genotype was 0.8766, and AA genotype was 0.8750.The rs5853783 and rs73158510 SNPs in the 3'UTR region of the PTX3 gene are associated with the risk of preeclampsia in a Chinese Han population.


Assuntos
Regiões 3' não Traduzidas/genética , Proteína C-Reativa/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Componente Amiloide P Sérico/genética , Adolescente , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , China/etnologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pré-Eclâmpsia/etnologia , Gravidez , Fatores de Risco
3.
Cancer Sci ; 111(3): 891-906, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31943575

RESUMO

Upstream ORF (uORF) is a translational initiation element located in the 5'UTR of eukaryotic mRNAs. Studies have found that uORFs play an important regulatory role in many diseases. Based on The Cancer Genome Atlas database, the results of our experiments and previous research evidence, we investigated transcription factor AP-4 (TFAP4) and its uORF, LIM and SH3 protein 1 (LASP1), long noncoding RNA 00520 (LINC00520), and microRNA (miR)-520f-3p as candidates involved in glioma malignancy, which is a poorly understood process. Both TFAP4-66aa-uORF and miR-520f-3p were downregulated, and TFAP4, LASP1, and LINC00520 were highly expressed in glioma tissues and cells. TFAP4-66aa-uORF or miR-520f-3p overexpression or TFAP4, LASP1, or LINC00520 knockdown inhibited glioma cell proliferation, migration, and invasion, but promoted apoptosis. TFAP4-66aa-uORF inhibited the translation of TFAP4 by binding to the TFAP4 mRNA. MicroRNA-520f-3p inhibited TFAP4 expression by binding to its 3'UTR. However, LINC00520 could promote the expression of TFAP4 by competitively binding to miR-520f-3p. In addition, TFAP4 transcriptionally activated LASP1 and LINC00520 expression by binding to their promoter regions, forming a positive feedback loop of TFAP4/LINC00520/miR-520f-3p. Our findings together indicated that TFAP4-66aa-uORF inhibited the TFAP4/LINC00520/miR-520f-3p feedback loop by directly inhibiting TFAP4 expression, subsequently leading to inhibition of glioma malignancy. This provides a basis for developing new therapeutic approaches for glioma treatment.


Assuntos
Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Glioma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
4.
Microbes Environ ; 35(1)2020.
Artigo em Inglês | MEDLINE | ID: mdl-31969530

RESUMO

MicroRNAs (miRNAs) are a group of small non-coding RNAs that suppress the expression of target mRNAs. The seed sequence of miRNA plays a crucial role in recognizing the 3'-untranslated region of the target mRNA. Cells infected with a simian foamy virus (SFV) isolated from an African green monkey (Chlorocebus aethiops) (SFVcae) showed high expression levels of viral miRNAs encoded in the long terminal repeat of SFVcae. In the present study, we investigated the roles and expression of miRNAs derived from an SFV isolated from a Japanese macaque (Macaca fuscata) (SFVmfu) using next-generation sequencing technologies. The results obtained showed that SFVmfu also expressed viral miRNAs; however, the seed sequences of most miRNAs derived from SFVmfu differed from those reported previously from SFVcae. Cells persistently infected with SFVmfu strongly expressed an miRNA with the same seed sequence as the miR-1 microRNA precursor family. Luciferase reporter assays indicated that this miRNA down-regulates the expression of adenylyl cyclase-associated protein 1, which is up-regulated in several solid tumors. The present results suggest that SFVmfu utilizes viral miRNAs to establish long-term co-existence with the Japanese macaque.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , RNA Viral/genética , Infecções por Retroviridae/virologia , Spumavirus/genética , Regiões 3' não Traduzidas , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular , Humanos , MicroRNAs/metabolismo , RNA Viral/metabolismo , Infecções por Retroviridae/genética
5.
J Agric Food Chem ; 68(2): 530-540, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31891490

RESUMO

The influence of ß-hydroxy-ß-methylbutyrate (HMB) on proliferation and differentiation of myogenic cells has been well-studied. However, the role of HMB in myofiber specification and potential mechanisms is largely unknown. Thus, the objective of this research was to explore the role of HMB supplementation in myofiber specification. Results showed that HMB treatment significantly increased the fast MyHC protein level (mice: 1.59 ± 0.08, P < 0.01; C2C12: 2.26 ± 0.11, P < 0.001), decreased the slow MyHC protein level (mice: 0.76 ± 0.05, P < 0.05; C2C12: 0.52 ± 0.02, P < 0.001), and increased the miR-199a-3p level (mice: 4.93 ± 0.37, P < 0.001; C2C12: 11.25 ± 0.57, P < 0.001). Besides, we also observed that HMB promoted the activity of glycolysis-related enzymes and reduced the activities of oxidation-related enzymes in mice and C2C12 cells. Overexpression of miR-199a-3p downregulated the slow MyHC protein level (0.71 ± 0.02, P < 0.01) and upregulated the fast MyHC protein level (2.13 ± 0.09, P < 0.001), while repression of miR-199a-3p exhibited the opposite effect. Target identification results verified that miR-199a-3p targets the 3'UTR of the TEA domain family member 1 (TEAD1) to cause its post-transcriptional inhibition (0.41 ± 0.07, P < 0.01). Knockdown of TEAD1 exhibited a similar effect with miR-199a-3p on myofiber specification. Moreover, suppression of miR-199a-3p blocked slow-to-fast myofiber type transition induced by HMB. Together, our finding revealed that miR-199-3p is induced by HMB and contributes to the action of HMB on slow-to-fast myofiber type conversion via targeting TEAD1.


Assuntos
MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Valeratos/farmacologia , Regiões 3' não Traduzidas , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , MicroRNAs/genética , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
J Biochem Mol Toxicol ; 34(2): e22426, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31777165

RESUMO

The purpose of this study was to investigate the biological effect of miR-16 on myocarditis and the underlying molecular mechanism. H9c2 cells were treated with 10 µg/mL lipopolysaccharide (LPS) for 12 hours to form a myocarditis injury model. We observed that LPS treatment distinctly decreased the level of miR-16 in H9c2 cells. Upregulation of miR-16 increased cell proliferation and reduced cell apoptosis. Then, CD40 was predicted and verified as a target gene of miR-16 by TargetScan and luciferase reporter assay, respectively. Furthermore, the messenger RNA and protein expression of CD40 are negatively regulated by miR-16. The relative expression of inflammatory factors was dramatically decreased by the miR-16 mimic. Cells cotransfected with miR-16 mimic and si-CD40 could significantly abolish the injury of cardiomyocytes caused by myocarditis. Our study illustrated that the upregulation of miR-16 has a protective effect on LPS-damaged H9c2 cells, which may be achieved by regulating CD40 and the nuclear factor kappa B pathway.


Assuntos
Antígenos CD40/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/metabolismo , Miocardite/induzido quimicamente , Miocardite/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Sítios de Ligação , Biomarcadores/metabolismo , Antígenos CD40/genética , Linhagem Celular , Técnicas de Silenciamento de Genes , Lipopolissacarídeos/efeitos adversos , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/genética , Transfecção
7.
Anim Genet ; 51(1): 117-121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31625179

RESUMO

Insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) is involved in the Hedgehog pathway and has been shown to regulate the RNA stability of several growth-related target genes. It is located in a quantitative trait locus showing a strong association with traits related to body size in ducks. Fibroblast growth factor receptor 1 (FGFR1) also participates in Hedgehog signaling pathways and has been reported to be associated with organic growth and development. FGFR1-knockout mice have been shown to have severe postnatal growth defects, including an approximately 50% reduction in body weight and bone mass. Meanwhile, nonsense-mediated mRNA decay factor (SMG6) can maintain genomic stability, which is associated with organic growth and development. Therefore, we hypothesized that IGF2BP1, FGFR1 and SMG6 genes may play important roles in the growth traits of goats. In this study, the existence of two insertion/deletion (InDel) variants within IGF2BP1, one InDel within FGFR1 and two InDels within SMG6 was verified and their correlation with growth traits was analyzed in 2429 female Shaanbei white cashmere goats. Results showed both the 15 bp InDel in intron 2 and the 5 bp InDel in the 3' regulatory region within IGF2BP1 were significantly associated with growth traits (P < 0.05) and goats with the combinatorial homozygous insertion genotypes of these two loci had the highest body weight (P = 0.046). The other InDels within FGFR1 and SMG6 were not obviously associated with growth traits (P > 0.05). Therefore, the two InDels in IGF2BP1 were vital mutations affecting goat growth traits.


Assuntos
Regiões 3' não Traduzidas , Cabras/genética , Mutação INDEL , Íntrons , Proteínas de Ligação a RNA/genética , Animais , Peso Corporal , Cruzamento , Feminino , Genótipo , Cabras/crescimento & desenvolvimento
8.
J Biochem Mol Toxicol ; 34(2): e22423, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729781

RESUMO

MicroRNAs are endogenous small noncoding RNAs that posttranscriptionally regulate the expression of target genes and play crucial roles in diverse physiopathologic processes. In the current study, we examined the microRNA (miRNA) expression profile of high-glucose-treated neonatal rat cardiomyocytes and the potential mechanisms. Differentially expressed miRNAs were analyzed by a miRNA microarray and validated by a quantitative real-time polymerase chain reaction in high-glucose-treated rat cardiomyocytes. Based on the results of our previous study and the bioinformatics prediction, we identified miR-195-5p/SGK1/Nedd4-2/hERG as the top-ranked signal pathway in diabetes cell model in vitro. In summary, our present study provides novel insights into the regulatory mechanism of miR-195-5p/SGK1/Nedd4-2/hERG in rat cardiomyocytes under high-glucose stress, which may provide a novel idea for the development of diagnostic and therapeutic strategies for diabetic cardiomyopathy in the future.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Glucose/farmacologia , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Transcriptoma , Regiões 3' não Traduzidas/genética , Animais , Sítios de Ligação , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Imediatamente Precoces/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Transfecção
9.
Cancer Sci ; 111(2): 713-726, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782868

RESUMO

There is an urgent need to find novel potential therapeutic targets for the diagnosis and treatment of clear cell renal cell carcinoma (ccRCC) due to its highly invasive ability as a common urological malignant tumor. Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression. We first used qRT-PCR analysis to find dysregulated circRNAs in ccRCC. A novel circRNA, hsa_circ_001895, was upregulated in ccRCC specimens and associated with metastatic properties of ccRCC. However, the tumorigenic mechanism of hsa_circ_001895 on ccRCC is yet to be found. We first indicated that hsa_circ_001895 predicted a poor prognosis in ccRCC patients. Additionally, overexpression of hsa_circ_001895 not only promoted cell proliferation, invasion and migration of ccRCC, but also inhibited cell apoptosis, whereas hsa_circ_001895 knockdown reversed the effect on ccRCC progression. In vivo s.c. xenotransplanted tumor model also showed that silencing hsa_circ_001895 could suppress in vivo ccRCC growth. Mechanistically, hsa_circ_001895 directly binds with microRNA (miR)-296-5p and inhibits its expression. Moreover, sex determining region Y (SRY)-box 12 (SOX12) was identified as a target of miR-296-5p, the expression of which was suppressed by miR-296-5p. Notably, the inhibitory effect of hsa_circ_001895 on ccRCC progression was reversed by miR-296-5p inhibitor. In general, our findings indicated that hsa_circ_001895 may sponge miR-296-5p and promote SOX12 expression, which is the underlying mechanism of hsa_circ_001895-induced ccRCC progression.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , MicroRNAs/genética , Fatores de Transcrição SOXC/genética , Regiões 3' não Traduzidas , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Masculino , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico
10.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 49-57, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31828293

RESUMO

Gastric cancer (GC) is one of malignant tumors with high mortality and morbidity in the world. MicroRNA-122 (miR-122) acts as a tumor suppressor in a variety of cancers and has been found to be dominant in gastric adenocarcinoma. However, the specific biological function of miR-122-5p in GC is not completely clear. In this study, we found that miR-122-5p was low-expressed in GC tissues and cell lines by using qRT-PCR. Overexpression of miR-122-5p inhibited the proliferation, migration, and invasion of GC cells by using CCK-8 and transwell assays. On the contrary, downregulation of miR-122-5p promoted the proliferation, migration, and invasion of GC cells. In addition, we found that the expression of LYN, an Src family tyrosine kinase, was inversely correlated with miR-122-5p expression in GC tissues by using western blot analysis, immunohistochemistry, and qRT-PCR assays. Meanwhile, luciferase assay results indicated that LYN is a direct target of miR-122-5p in GC cells. Moreover, silencing LYN expression by its siRNA inhibited the proliferation, migration, and invasion of GC cells. Importantly, overexpression of LYN restored miR-122-5p-mediated inhibition of the proliferation, migration, and invasion of GC cells. Taken together, our results indicated miR-122-5p inhibited the proliferation, migration, and invasion by targeting LYN in GC.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Neoplasias Gástricas/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mimetismo Molecular/genética , Mutação , RNA Interferente Pequeno/genética , Neoplasias Gástricas/patologia , Transfecção
11.
Cancer Sci ; 111(2): 369-382, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833612

RESUMO

The androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18-24 months of AR blocking therapy, patients invariably progress to castration-resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA-binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3'-untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2-AR axis and provide novel evidence towards a strategy against prostate cancer.


Assuntos
Neoplasias da Próstata/patologia , Proteínas de Ligação a RNA/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Gradação de Tumores , Transplante de Neoplasias , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Estabilidade de RNA , Receptores Androgênicos/química , Regulação para Cima
12.
Arch Virol ; 165(2): 345-354, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31834525

RESUMO

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a typical neurotropic coronavirus that mainly invades the central nervous system (CNS) in piglets and causes vomiting and wasting disease. Emerging evidence suggests that PHEV alters microRNA (miRNA) expression profiles, and miRNA has also been postulated to be involved in its pathogenesis, but the mechanisms underlying this process have not been fully explored. In this study, we found that PHEV infection upregulates miR-142a-3p RNA expression in N2a cells and in the CNS of mice. Downregulation of miR-142a-3p by an miRNA inhibitor led to a significant repression of viral proliferation, implying that it acts as a positive regulator of PHEV proliferation. Using a dual-luciferase reporter assay, miR-142a-3p was found to bind directly bound to the 3' untranslated region (3'UTR) of Rab3a mRNA and downregulate its expression. Knockdown of Rab3a expression by transfection with an miR-142a-3p mimic or Rab3a siRNA significantly increased PHEV replication in N2a cells. Conversely, the use of an miR-142a-3p inhibitor or overexpression of Rab3a resulted in a marked restriction of viral production at both the mRNA and protein level. Our data demonstrate that miR-142a-3p promotes PHEV proliferation by directly targeting Rab3a mRNA, and this provides new insights into the mechanisms of PHEV-related pathogenesis and virus-host interactions.


Assuntos
Betacoronavirus 1/genética , Proliferação de Células/genética , Infecções por Coronavirus/genética , MicroRNAs/genética , Suínos/virologia , Proteína rab3A de Ligação ao GTP/genética , Regiões 3' não Traduzidas/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Regulação para Baixo/genética , Células HEK293 , Humanos , Camundongos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Regulação para Cima/genética
13.
Cell Mol Life Sci ; 77(2): 351-363, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31222373

RESUMO

Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Estilbenos/farmacologia , Regiões 3' não Traduzidas/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco , Transcrição Genética/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismo , Neoplasias da Bexiga Urinária
14.
Gene ; 723: 143986, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323309

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Accumulating evidence shows that microRNAs play important roles in diabetic kidney. However, the potential role of MicroRNA-544 (miR-544) in DN remains unclear. In this study, we explored the role of miR-544 on inflammation and fibrosis in diabetic kidney using db/db mice. Renal expression of miR-544 was decreased in mice, companied by increased the expression of FASN. The dual luciferase assay confirmed FASN as a direct target of miR-544. Over-expression of miR-544 significantly ameliorated renal injury, mesangial matrix and renal fibrosis. In addition, over-expression of miR-544 significantly attenuated inflammatory cells infiltration and IL-1, IL-6, TNF- and iNOS production in DN. Furthermore, miR-544 over-expression inhibited the activation of NF-kB signal pathway in DN. In conclusion, our finding demonstrated that miR-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN, suggesting that miR-544 might have therapeutic potential for the treatment of DN.


Assuntos
Citocinas/metabolismo , Nefropatias Diabéticas/genética , Ácido Graxo Sintase Tipo I/genética , MicroRNAs/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Regiões 3' não Traduzidas , Animais , Nefropatias Diabéticas/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Células HEK293 , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Camundongos , NF-kappa B/metabolismo , Receptores para Leptina/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
15.
Gene ; 724: 144144, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629819

RESUMO

BACKGROUND/AIMS: Rheumatoid arthritis synovial fibroblasts (RASF) play an essential role in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the biological effects of miR-22 on RASFs. METHODS: RT-qPCR was used to detect the expressions of miR-22 and SIRT1 in RA synovial tissue. The results of miR-22 on the proliferation of RASF were examined by MTT assay. The effects of miR-22 on the secretion of TNF-α, IL-1ß, and IL-6 in RASF were measured by ELISA. Target gene prediction and screening, and luciferase reporter assay were used to testify downstream target genes of miR-22. RT-qPCR and western blotting were used to detect the mRNA and protein expression of SIRT1. RESULTS: miR-22 was significantly decreased in RA synovial tissue, while SIRT1 was significantly increased in RA synovial tissue. Over-expression of miR-22 significantly inhibited the proliferation of RASFs and the secretions of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in RASFs. SIRT1 was identified as a direct target of miR-22. Over-expression of miR-22 reduced the expression level of SIRT1 in RASFs. Over-expression of SIRT1 reversed the effect of miR-22 on the proliferation of RASFs and the secretion of inflammatory cytokines. CONCLUSION: MIR-22 was significantly down-regulated in RASF cells, which affected the secretions of inflammatory cytokines and cell proliferation by regulating SIRT1.


Assuntos
Artrite Reumatoide/genética , Citocinas/metabolismo , MicroRNAs/genética , Sirtuína 1/genética , Membrana Sinovial/patologia , Regiões 3' não Traduzidas , Artrite Reumatoide/patologia , Proliferação de Células/genética , Citocinas/genética , Feminino , Fibroblastos/patologia , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Sirtuína 1/metabolismo , Membrana Sinovial/metabolismo
16.
Gene ; 724: 144146, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31634561

RESUMO

miRNA mediated genetic regulation is widely involved in carcinogenesis of cervical cancer. In this study, miR-214 was confirmed to directly regulate MKK3 via imperfect base-pairing to its 3'UTR, resulting down-regulation of its expression level. Compared to normal tissues, a down-regulated level of miR-214 was observed in cervical cancer, while MKK3 was up-regulated. Next, we demonstrated that over-expression of miR-214 or knockdown of MKK3 can inhibit the growth, proliferation, invasion and migration of cervical cancer in vitro and in vivo. Moreover, the effects of miR-214 in HeLa cells were rescued by the restoration of MKK3. In conclusion, our results laid new foundations for investigating the pathogenesis and diagnosis of cervical cancer.


Assuntos
MAP Quinase Quinase 3/genética , MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Regiões 3' não Traduzidas , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , MAP Quinase Quinase 3/metabolismo , Camundongos Nus , MicroRNAs/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Clin Pathol ; 73(1): 14-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31434698

RESUMO

AIMS: Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability). METHODS: A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II ß-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes. RESULTS: All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A]. CONCLUSIONS: This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.


Assuntos
Regiões 3' não Traduzidas , Mutação , Polimorfismo Genético , Estabilidade de RNA , RNA Mensageiro/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Fenótipo , RNA Mensageiro/metabolismo , Fatores de Risco , alfa-Globinas/metabolismo , Talassemia alfa/sangue , Talassemia alfa/diagnóstico
18.
Gene ; 729: 144319, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884108

RESUMO

In previous study, we have found that microRNA-23a is down regulated in atherosclerotic tissues. Here we demonstrate that miR-23a directly binds to 3'UTR of HSP90 mRNA to suppress the expression of HSP90. To investigate the potential roles of miR-23a in macrophage, THP-1 macrophages were transfected with miR-23a mimics or inhibitors. Our results showed inflammatory factors IL-6 and MCP-1 concentrations in cell culture medium of macrophage and foam cell transfected with miR-23a mimics were decreased. Furthermore, we find that apoptosis of macrophage and foam cells transfected with miR-23a mimics were inhibited. Over expression of miR-23a in foam cells could reduced lipid intake and accumulation in foam cells. Meanwhile, we found that in inflammatory macrophages and foam cells transfected with miR-23a mimcs, HSP90 and NF-κB proteins are significantly decreased. Our results have suggested a promising and potential therapeutic target for atherosclerosis.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Células Espumosas/patologia , Proteínas de Choque Térmico HSP90/genética , Macrófagos/patologia , MicroRNAs/genética , Regiões 3' não Traduzidas , Apoptose/genética , Aterosclerose/metabolismo , Proliferação de Células/genética , Células Espumosas/metabolismo , Humanos , Inflamação/genética , Macrófagos/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Células THP-1
19.
Cancer Sci ; 111(3): 869-880, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883160

RESUMO

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer-related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR-493-5p, a major tumor suppressor miRNA that inactivates miR-483-3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR-493-5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR-493-5p given its significant inhibition through 3'-UTR targeting in miR-493-5p-rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR-493-5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR-493-5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR-493-5p activity. In summary, miR-493-5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Proteína Proto-Oncogênica N-Myc/genética , Oncogenes/genética , Regiões 3' não Traduzidas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs , Pessoa de Meia-Idade , Prognóstico , Proto-Oncogenes/genética
20.
Nucleic Acids Res ; 48(4): 2126-2143, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31863581

RESUMO

Small noncoding RNAs (sRNAs) from mRNA 3' UTRs seem to present a previously unrecognized layer of bacterial post-transcriptional control whereby mRNAs influence each other's expression, independently of transcriptional control. Studies in Escherichia coli and Salmonella enterica showed that such sRNAs are natural products of RNase E-mediated mRNA decay and associate with major RNA-binding proteins (RBPs) such as Hfq and ProQ. If so, there must be additional sRNAs from mRNAs that accumulate only under specific physiological conditions. We test this prediction by characterizing candidate NarS that represents the 3' UTR of nitrate transporter NarK whose gene is silent during standard aerobic growth. We find that NarS acts by Hfq-dependent base pairing to repress the synthesis of the nitrite transporter, NirC, resulting in mRNA cross-regulation of nitrate and nitrite transporter genes. Interestingly, the NarS-mediated repression selectively targets the nirC cistron of the long nirBDC-cysG operon, an observation that we rationalize as a mechanism to protect the bacterial cytoplasm from excessive nitrite toxicity during anaerobic respiration with abundant nitrate. Our successful functional assignment of a 3' UTR sRNA from a non-standard growth condition supports the notion that mRNA crossregulation is more pervasive than currently appreciated.


Assuntos
Proteínas de Transporte de Ânions/genética , Proteínas de Escherichia coli/genética , Fator Proteico 1 do Hospedeiro/genética , Metiltransferases/genética , Pequeno RNA não Traduzido/genética , Regiões 3' não Traduzidas/genética , Endorribonucleases/genética , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Nitratos/metabolismo , Óperon/genética , Processamento Pós-Transcricional do RNA/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Respiração/genética , Salmonella enterica/genética
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