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1.
Crit Rev Eukaryot Gene Expr ; 32(4): 31-40, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35695663

RESUMO

Gastric cancer (GC) is a malignancy of the digestive tract with rapid progress, poor prognosis, and low survival rate. The aberrant expression of microRNA (miRNA) is closely related to the tumorigenesis and progression of GC. The purpose of this study was to investigate the effects of miR-137 on the proliferation, apoptosis, and migration of GC cells. Bioinformatics analysis revealed that EZH2 expression in GC based on The Cancer Genome Atlas (TCGA) dataset was dramatically increased, miR-137 expression was down-regulated, and miR-137 was remarkably negatively correlated with EZH2 in GC. Next, it was found that EZH2 expression was significantly increasing and miR-137 was significantly decreasing by quantitative polymerase chain reaction (qRT-PCR) in GC clinical specimens. In addition, miR-137 expression in GC cell lines was significantly lower than that in normal gastric parietal cells. TargetScan and star-Base were employed to predict that EZH2 was a potential target of miR-137, and subsequent luciferase reports confirmed this prediction. Western blot assay demonstrated that up-regulation of miR-137 decreased EZH2 expression in BGC-823 cells, whereas silenced miR-137 enhanced EZH2 expression in SGC-7901 cells. The gain/loss-of-function indicates that miR-137 regulates the proliferation, apoptosis, migration and epithelial-mesenchymal transition of GC cells. In conclusion, our findings indicate that miR-137 restrains migration and proliferation and induces apoptosis partially through negatively regulating the expression of EZH2 in GC cells.


Assuntos
MicroRNAs , Neoplasias Gástricas , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/fisiologia , Neoplasias Gástricas/metabolismo
2.
J Invest Dermatol ; 142(10): 2570-2579.e6, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35483653

RESUMO

Although small extracellular vesicles (sEV) have been reported to play an important role in cellular senescence and aging, little is known about the potential role and function of microRNAs (miRNAs) contained within the sEV. To determine the senescence-associated factors secreted from sEV of human dermal fibroblasts (HDFs), we isolated and characterized sEV from nonsenescent versus that from senescent HDFs. Small RNA-sequencing analysis identified many enriched miRNAs in sEV of senescent HDF, as shown by the upregulation of miR-10a, miR-30c, and miR-451a and downregulation of miR-128, miR-184, miR-200c, and miR-125a. Overexpression of miR-10a, miR-30c, and miR-451a induced an aging phenotype in HDFs, whereas inhibition of these miRNAs reduced senescent-like phenotypes in senescent HDFs. Moreover, treatment with sEV or sEV-containing conditioned medium promoted cellular senescence in HDFs, whereas sEV depletion abrogated prosenescence effects of the senescent HDF secretome. Interestingly, prosenescence sEV miRNAs were found to have an essential role in regulating ROS production and mitophagy activation. Taken together, our results revealed miR-10a, miR-30c, and miR-451a as prosenescence factors that are differentially expressed in sEV of senescent HDFs, showing the essential role of sEV miRNAs in the biological processes of aging.


Assuntos
Vesículas Extracelulares , MicroRNAs , Senescência Celular/fisiologia , Meios de Cultivo Condicionados , Fibroblastos , Humanos , MicroRNAs/fisiologia , Espécies Reativas de Oxigênio
3.
Oncol Rep ; 47(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35322861

RESUMO

MicroRNAs (miRNAs/miRs), non­coding single­stranded RNAs of length 18­24 nucleotides, can modulate gene expression through post­transcriptional control. As such, they can influence tumor proliferation, apoptosis, invasion, metastasis as well as chemotherapy resistance by regulating certain downstream genes. In this context, miR­200b­3p, one particular member of the miR­200 family, possesses the ability to suppress tumor progression. However, many studies have suggested that, in certain cases, this miRNA may also promote the development of some tumors due to differences in the microenvironments and molecular backgrounds of different cancers. This review summarizes previous studies on the involvement of miR­200b­3p in tumors, including the underlying mechanism.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/fisiologia , Neoplasias/genética , Microambiente Tumoral/genética
4.
Pharm Biol ; 60(1): 652-663, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35311466

RESUMO

CONTEXT: Berberine has myocardial protective effects. OBJECTIVES: The protective effects of berberine on heart ischemia-reperfusion (I/R) injury were explored. MATERIALS AND METHODS: Human cardiomyocytes were divided into control group, oxygen-glucose deprivation/re-oxygen (OGD/R) (2 h OGD with 24 h reoxygenation) group, OGD/R + low group (5 µM berberine for 24 h) and OGD/R + high group (10 µM berberine for 24 h). Twenty-four Wistar rats were divided into sham group, I/R group (45 min occlusion with 2 h reperfusion), I/R + berberine group (50 mg/kg berberine 1 h before I/R surgery) and I/R + berberine + antagomir (intraperitoneally injected with miR-26b-5p antagomir). MicroRNA profile, effects of berberine on I/R or OGD/R-induced injuries, and the role of miR-26b-5p in the function of berberine were explored. RESULTS: OGD/R treatment suppressed viability (0.41 ± 0.05 vs. 0.87 ± 0.13, p< 0.05), while induced apoptosis (6.6 ± 1.0% vs. 26.3 ± 4.8%, p< 0.05) in cardiomyocytes, which was restored by berberine (viability: 0.64 ± 0.01 for 5 µM and 0.72 ± 0.01 for 10 µM, p< 0.05; apoptosis: 10.9 ± 2.2 for 5 µM and 7.9 ± 1.3 for 10 µM). Berberine induced miR-26b-5p and inhibited PTGS2/MAPK pathway. MiR-26b-5p inhibition counteracted the protective function of berberine. In rats, berberine (50 mg/kg) improved heart histological structure and suppressed inflammatory response, which was impaired by miR-26b-5p inhibition. DISCUSSION AND CONCLUSIONS: Berberine exerted anti-I/R function in heart by inducing miR-26b-5p and suppressing the PTGS2/MAPK pathway. These data promote the application of berberine as an anti-I/R agent.


Assuntos
Berberina/farmacologia , Ciclo-Oxigenase 2/fisiologia , Inflamação/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/fisiologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , MicroRNAs/análise , Ratos , Ratos Wistar
5.
Clin Sci (Lond) ; 136(5): 323-328, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35234251

RESUMO

MicroRNAs (miRNAs), which are regarded as crucial regulators of gene expression and diverse aspects of cell biology, can be present in various body fluids as highly stable molecules. It is also known that miRNAs exert tissue-specific regulation of gene transcription. Large amount of clinical and experimental evidence provided the rationale for raising the intriguing question of whether miRNAs can mediate cell-cell communication. For those reasons, miRNAs have been considered as the 'Holy Grail' of biomarkers allowing non-invasive diagnostic screening and early detection of a variety of diseases, including solid and non-solid cancers. In a study published in Clin. Sci. (Lond.) (2011) 120(5):183-193 (https://doi.org/10.1042/CS20100297), Gui et al. investigated the hypothesis that circulating miRNAs could be used to identify patients with liver pathologies. Specifically, the authors profiled circulating miRNAs in patients with hepatocellular carcinoma (HCC), liver cirrhosis (LC), and healthy controls and found that serum miR-885-5p levels were significantly higher in samples of patients with HCC (6.5-fold increase) and LC (8.8-fold increase). In this commentary, we highlight biological aspects associated with mir-122-the 'liver-specific' miRNA, which has been associated with a diverse range of liver pathologies. In addition, we discuss the relevance of mir-885-5p as potential biomarker for detecting human cancers. Finally, we provide some clues about how presumably unrelated miRNAs such as miR-122 and miR-885-5p may act in similar biological processes (BPs), making the miRNA regulatory networks more complex than anticipated.


Assuntos
Neoplasias Hepáticas/etiologia , MicroRNAs/fisiologia , Animais , Biomarcadores Tumorais , Montagem e Desmontagem da Cromatina , Humanos , Camundongos , MicroRNAs/análise , MicroRNAs/sangue
6.
Domest Anim Endocrinol ; 80: 106711, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35338828

RESUMO

Fat content is an important index to evaluate the individual performance of livestock animals such as sheep for meat production purposes. Reducing the subcutaneous and visceral fat while increasing the intramuscular fat is a valuable goal to achieve for the meat production industry. Here, we investigated the effect of miR-128-1-5p on adipogenesis of subcutaneous fat by targeting 5'-UTR in KLF11, a rare mechanism where most miRNAs bind the 3'-UTR of mRNAs. A dual fluorescence reporter assay was conducted to validate the binding sites of miR-128-1-5p on 5'-UTR of KLF11 mRNA. Roles of miR-128-1-5p in KLF11 expression were measured through co-transfecting miRNA mimics with KLF11-expressing vectors (CDSs together with or without the 5'-UTR) into ovine stromal vascular fractions (SVF). Additionally, functional roles of miR-128-1-5p, and KLF11 in adipogenesis of ovine subcutaneous fat were investigated. Results showed that miR-128-1-5p targeted KLF11 5'-UTR, reduced the fluorescence activity of the dual fluorescent reporter vector, as well as KLF11 mRNA, and protein expression levels. During the differentiation of SVF, disturbing the expression of miR-128-1-5p and KLF11 changed the adipogenic differentiation of SVF as observed in the lipid formation, and adipogenic marker genes. This study indicates that miR-128-1-5p promotes the expression of lipogenic marker genes and the formation of lipid droplets by targeting KLF11 5'-UTR. Furthermore, overexpression, and inhibition of KLF11 indicate that KLF11 inhibited SVF differentiation. In summary, the 5'-UTR binding mechanism discovered in this study extends the understanding of miRNA functions. Key roles of miR-128-1-5p and KLF11 in the adipogenesis of sheep subcutaneous fat have potential values for improving the meat and/or fat ratio of domestic animals.


Assuntos
MicroRNAs , Regiões 3' não Traduzidas , Adipogenia/genética , Animais , Diferenciação Celular , MicroRNAs/fisiologia , RNA Mensageiro , Ovinos/genética
7.
Biochem Biophys Res Commun ; 604: 88-95, 2022 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-35303684

RESUMO

Circular RNAs (circRNAs), characterized as single-stranded closed circular RNA molecules, have been established to exert pivotal functions in various biological or pathological processes. Nonetheless, the effects and underlying mechanisms concerning circRNAs on the aging and aging-related diseases remain elusive. We herein compared the expression patterns of circRNAs in young and senescent mouse embryonic fibroblasts (MEFs), and uncovered that circRNF169 was dramatically up-regulated in senescent MEFs compared with that in young MEFs. Therefore, we further digged into the role and potential mechanisms of circRNF169 in the senescence of MEFs. The results of senescence-associate-ß-galactosidase staining and BrdU incorporation assay showed that silencing of circRNF169 significantly delayed MEFs senescence and promoted cell proliferation, while ectopic expression of circRNF169 exhibited the opposite effects. Moreover, the dual-luciferase reporter assay confirmed that circRNF169 acted as an endogenous miR-30c-5p sponge, which accelerated cellular senescence by sequestering and inhibiting miR-30c-5p activity. Taken together, our results suggested that circRNF169 exerted a crucial role in cellular senescence through sponging miR-30c-5p and represented a promising target for aging intervention.


Assuntos
Senescência Celular , MicroRNAs , RNA Circular , Animais , Proliferação de Células/genética , Senescência Celular/genética , Fibroblastos/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/fisiologia , RNA Circular/genética , RNA Circular/fisiologia
8.
Clin. transl. oncol. (Print) ; 24(3): 503-516, marzo 2022. tab, graf
Artigo em Inglês | IBECS | ID: ibc-203545

RESUMO

PurposeLysophosphatidic acid (LPA) is a bioactive molecule which participates in many physical and pathological processes. Although LPA receptor 6 (LPAR6), the last identified LPA receptor, has been reported to have diverse effects in multiple cancers, including breast cancer, its effects and functioning mechanisms are not fully known.MethodsMultiple public databases were used to investigate the mRNA expression of LPAR6, its prognostic value, and potential mechanisms in breast cancer. Western blotting was performed to validate the differential expression of LPAR6 in breast cancer tissues and their adjacent tissues. Furthermore, in vitro experiments were used to explore the effects of LPAR6 on breast cancer. Additionally, TargetScan and miRWalk were used to identify potential upstream regulating miRNAs and validated the relationship between miR-27a-3p and LPAR6 via real-time polymerase chain reaction and an in vitro rescue assay.ResultsLPAR6 was significantly downregulated in breast cancer at transcriptional and translational levels. Decreased LPAR6 expression in breast cancer is significantly correlated with poor overall survival, disease-free survival, and distal metastasis-free survival, particularly for hormone receptor-positive patients, regardless of lymph node metastatic status. In vitro gain and loss-of-function assays indicated that LPAR6 attenuated breast cancer cell proliferation. The analyses of TCGA and METABRIC datasets revealed that LPAR6 may regulate the cell cycle signal pathway. Furthermore, the expression of LPAR6 could be positively regulated by miR-27a-3p. The knockdown of miR-27a-3p increased cell proliferation, and ectopic expression of LPAR6 could partly rescue this phenotype.ConclusionLPAR6 acts as a tumor suppressor in breast cancer and is positively regulated by miR-27a-3p.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , MicroRNAs/fisiologia , Células Tumorais Cultivadas , Receptores de Ácidos Lisofosfatídicos
9.
Clin. transl. oncol. (Print) ; 24(3): 546-555, marzo 2022.
Artigo em Inglês | IBECS | ID: ibc-203549

RESUMO

ObjectiveAccumulating evidence has been revealed that miR-590 is involved in the progression and carcinogenesis of various cancers. However, the molecular mechanism of miR-590 in non-small-cell lung cancer (NSCLC) remains unclear.MethodsQuantitative reverse transcription-PCR (qRT-PCR), western blot, MTT, and transwell assay were applied to investigate the functional role of miR-590 in this study. Dual luciferase reporter assay was utilized to investigate the interaction between YAP1 and miR-590 expression. Cells transfected with miR-590 mimic or inhibitor were subjected to western blot to investigate the role of Wnt/β-catenin signaling in NSCLC modulated by miR-590.ResultsMiR-590 was down-regulated in NSCLC tissues and cells. Kaplan–Meier analysis found that the higher expression of miR-590 in NSCLC patients, the more improved survival rate of NSCLC patients. Over-expression of miR-590 inhibited NSCLC cell proliferation, migration, and invasion. Moreover, increasing miR-590 suppressed Yes-associated protein 1 (YAP1) expression and inhibited the Wnt/β-catenin pathway in NSCLC cells. Furthermore, miR-590 was negatively correlated with YAP1 expression.ConclusionThese findings demonstrated that the miR-590/YAP1 axis exerted an important role in the progression of NSCLC, suggesting that miR-590 might be the appealing prognostic marker for NSCLC treatment.


Assuntos
Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Proteínas RGS/fisiologia , Células Tumorais Cultivadas , Via de Sinalização Wnt/fisiologia
10.
Sci Rep ; 12(1): 3074, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35197498

RESUMO

Alzheimer's disease (AD) is marked by neurofibrillary tangles and senile plaques composed of amyloid ß (Aß) peptides. However, specific contributions of different cell types to Aß deposition remain unknown. Non-coding microRNAs (miRNA) play important roles in AD by regulating translation of major associated proteins, such as Aß precursor protein (APP) and ß-site APP-cleaving enzyme (BACE1), two key proteins associated with Aß biogenesis. MiRNAs typically silence protein expression via binding specific sites in mRNAs' 3'-untranslated regions (3'-UTR). MiRNAs regulate protein levels in a cell-type specific manner; however, mechanisms of the variation of miRNA activity remain unknown. We report that miR-298 treatment reduced native APP and BACE1 protein levels in an astrocytic but not in a neuron-like cell line. From miR-298's effects on APP-3'-UTR activity and native protein levels, we infer that differences in APP 3'-UTR length could explain differential miR-298 activity. Such varied or truncated, but natural, 3'-UTR specific to a given cell type provides an opportunity to regulate native protein levels by particular miRNA. Thus, miRNA's effect tailoring to a specific cell type, bypassing another undesired cell type with a truncated 3'-UTR would potentially advance clinically-relevant translational research.


Assuntos
Regiões 3' não Traduzidas/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Variação Genética , MicroRNAs/genética , MicroRNAs/fisiologia , Biossíntese de Proteínas/genética , Linhagem Celular , Humanos
11.
Reprod Biol Endocrinol ; 20(1): 38, 2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35209928

RESUMO

Preeclampsia (PE), a pregnancy disorder that affects 5-7% of pregnant women, is among the primary causes for maternal and perinatal mortality. PE is believed to be associated with insufficient invasion of villous and extravillous trophoblasts (EVTs), which hampers uterine spiral artery remodeling and finally induces PE. But the mechanism responsible for reduction of trophoblast invasion remains unclear. In this study, placental tissues taken from healthy donors and PE patients were used to evaluate the miR-326 expression; CCK8 and colony formation assays were used to confirm the effect of miR-326 on cell proliferation; transwell assay was used to demonstrate the effect of miR-326 on cell invasion capability; western blot was used to investigate the underlying mechanism; and luciferase assay was used to detect the effect of miR-326 on YAP/TAZ-mediated transcription activity. It was revealed the miR-326 expression was higher in placentas from PE patients than from healthy donors. After transfection of miR-326 mimics, trophoblast proliferation and invasion were impaired. Using TargetScan, we speculated that PAX8 was a target of miR-326, which was later confirmed by western blot. The YAP/TAZ expression was also downregulated after transfection with miR-326. Luciferase assay demonstrated that overexpression of miR-326 suppressed YAP/TAZ-mediated transcription activity by targeting PAX8. Overexpression of PAX8 could partly rescue miR-326-induced suppression of trophoblast proliferation and invasion. Taken together, our result indicated that miR-326 suppresses trophoblast growth, invasion, and migration by means of targeting PAX8 via the Hippo pathway.


Assuntos
MicroRNAs/fisiologia , Fator de Transcrição PAX8/genética , Trofoblastos/fisiologia , Adulto , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Regulação para Baixo/genética , Feminino , Regulação da Expressão Gênica , Humanos , Gravidez
12.
BMC Urol ; 22(1): 14, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35109849

RESUMO

BACKGROUND: The important role of long noncoding RNAs (lncRNAs) in cancer has been demonstrated in many studies. Prostate cancer gene expression marker 1 (PCGEM1) is a lncRNA specifically expressed within the prostate and overexpressed in many cancer cells. Numerous studies have shown that PCGEM1 promotes cell proliferation, invasion and migration. However, the specific mechanism of PCGEM1 within prostate cancer (PCa) has not been elucidated. MicroRNA-506-3p (miR-506-3p) is a noncoding RNA, and studies have indicated that miR-506-3p is downregulated in prostate cancer cell lines and functions as a tumor suppressor. METHODS: The TCGA (GEPIA) database ( http://gepia.cancer-pku.cn/ ) was employed to measure PCGEM1 levels in PCa. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the PCGEM1 gene level. CCK-8 (Cell Counting Kit-8) and colony formation assays were used to detect cell proliferation, and Transwell assays were applied to assess cell invasion and migration. The interacting ability of miR-506-3p with PCGEM1 or TRIAP1 was validated through a dual-luciferase reporter assay. TRIAP1 protein expression was detected by Western blotting. RESULTS: PCGEM1 expression was increased in PCa tissues and cells. In PCa tissues, High PCGEM1 expression was associated with high Gleason score, distant metastasis and extracapsular extension. In addition, PCGEM1 knockdown inhibited PCa cell (C4-2B and PC-3) proliferation, invasion and migration. miR-506-3p may interact with PCGEM1 or TRIAP1, and the suppressive effect of PCGEM1 knockdown was reversed when TRIAP1 or a miR-506-3p inhibitor was cotransfected. CONCLUSION: PCGEM1 expression increased in PCa cells and tissues, enhancing PCa cell proliferation, migration and invasion by sponging miR-506 to upregulate TRIAP1.


Assuntos
Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Movimento Celular , Proliferação de Células , Humanos , Masculino , Modelos Animais , Invasividade Neoplásica , Prognóstico , Células Tumorais Cultivadas
13.
Sci Rep ; 12(1): 2889, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190587

RESUMO

Metformin inhibits oxidative phosphorylation and can be used to dissect metabolic pathways in colorectal cancer (CRC) cells. CRC cell proliferation is inhibited by metformin in a dose dependent manner. MicroRNAs that regulate metabolism could be identified by their ability to alter the effect of metformin on CRC cell proliferation. An unbiased high throughput functional screen of a synthetic micoRNA (miRNA) library was used to identify miRNAs that impact the metformin response in CRC cells. Experimental validation of selected hits identified miRNAs that sensitize CRC cells to metformin through modulation of proliferation, apoptosis, cell-cycle and direct metabolic disruption. Among eight metformin sensitizing miRNAs identified by functional screening, miR-676-3p had both pro-apoptotic and cell cycle arrest activity in combination with metformin, whereas other miRNAs (miR-18b-5p, miR-145-3p miR-376b-5p, and miR-718) resulted primarily in cell cycle arrest when combined with metformin. Investigation of the combined effect of miRNAs and metformin on CRC cell metabolism showed that miR-18b-5p, miR-145-3p, miR-376b-5p, miR-676-3p and miR-718 affected glycolysis only, while miR-1181 only regulated CRC respiration. MicroRNAs can sensitize CRC cells to the anti-proliferative effects of metformin. Identifying relevant miRNA targets may enable the design of innovative therapeutic strategies.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Metformina/farmacologia , MicroRNAs/fisiologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos
14.
Can J Physiol Pharmacol ; 100(2): 167-175, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35025607

RESUMO

Cardiac fibrosis is one of the major pathological characteristics of diabetic cardiomyopathy (DCM). MicroRNAs (miRNAs, miRs) have been identified as key regulators in the progression of cardiac fibrosis. This study aimed to investigate the role of miR-30a-5p in DCM and the underlying mechanism. The rat model of diabetes mellitus (DM) was established by streptozotocin injection, and the rat primary cardiac fibroblasts (CFs) were isolated from cardiac tissue and then treated with high glucose (HG). MTT assay was performed to assess the viability of CFs. Dual-luciferase reporter gene assay was conducted to verify the interaction between miR-30a-5p and Smad2. The expression of miR-30a-5p was downregulated in the myocardial tissues of DM rats and HG-stimulated CFs. Overexpression of miR-30a-5p reduced Smad2 levels and inhibited collagen formation in HG-stimulated CFs and DM rats, as well as decreased the proliferation of CFs induced by HG. Smad2 was a target of miR-30a-5p and its expression was inhibited by miR-30a-5p. Furthermore, the simultaneous overexpression of Smad2 and miR-30a-5p reversed the effect of miR-30a-5p overexpression alone in CFs. Our results indicated that miR-30a-5p reduced Smad2 expression and also induced a decrease in proliferation and collagen formation in DCM.


Assuntos
Proliferação de Células/genética , Colágeno/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Expressão Gênica , MicroRNAs/genética , MicroRNAs/fisiologia , Animais , Modelos Animais de Doenças , Masculino , MicroRNAs/metabolismo , Miocárdio/citologia , Ratos Sprague-Dawley , Proteína Smad2/genética , Proteína Smad2/metabolismo
15.
Plant Mol Biol ; 108(1-2): 93-103, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34982361

RESUMO

KEY MESSAGE: Proper root growth depends on the clearance of TCP transcripts from the root apical meristem by microRNA miR319. The evolutionarily conserved microRNA miR319 regulates genes encoding TCP transcription factors in angiosperms. The miR319-TCP module controls cell proliferation and differentiation in leaves and other aerial organs. The current model sustains that miR319 quantitatively tunes TCP activity during leaf growth and development, ultimately affecting its size. In this work we studied how this module participates in Arabidopsis root development. We found that misregulation of TCP activity through impairment of miR319 binding decreased root meristem size and root length. Cellular and molecular analyses revealed that high TCP activity affects cell number and cyclin expression but not mature cell length, indicating that, in roots, unchecking the expression of miR319-regulated TCPs significantly affects cell proliferation. Conversely, tcp multiple mutants showed no obvious effect on root growth, but strong defects in leaf morphogenesis. Therefore, in contrast to the quantitative regulation of the TCPs by miR319 in leaves, our data suggest that miR319 clears TCP transcripts from root cells. Hence, we provide new insights into the functions of the miR319-TCP regulatory system in Arabidopsis development, highlighting a different modus operandi for its action mechanism in roots and shoots.


Assuntos
Proteínas de Arabidopsis/fisiologia , MicroRNAs/fisiologia , Raízes de Plantas/crescimento & desenvolvimento , Fatores de Transcrição/fisiologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , MicroRNAs/metabolismo , Microscopia Confocal , Raízes de Plantas/metabolismo , Raízes de Plantas/ultraestrutura , Plantas Geneticamente Modificadas , Fatores de Transcrição/metabolismo , Transcriptoma
16.
Pathol Res Pract ; 229: 153734, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35030351

RESUMO

Clear cell renal cell carcinoma (ccRCC) is recognized as one of the most lethal malignancies among the urological system, with constantly increasing mortality. While the molecular mechanisms underlying ccRCC progression are still poorly understood, the molecular and functional role of lncRNA in multiple diseases has been well demonstrated. In this study, we hypothesized that lncRNA MEG8 might participate in ccRCC development. At first, we found that MEG8 expression was increased in ccRCC tumor tissues and cells. Next, we demonstrated that MEG8 knockdown suppressed cell viability, migration, and invasion in vitro and inhibited tumor growth in vivo. Subsequently, we utilized bioinformatics analysis, ChIP, and luciferase assays, and we found that PLAG1 could transcriptionally regulate MEG8 in ccRCC cells. Furthermore, MEG8 promoted G3BP1 expression to aggravate ccRCC tumorigenic properties through sponging miR-495-3p. Our study identified a novel PLAG1/MEG8/miR-495-3p/G3BP1 network in ccRCC development, which might be a promising direction for developing new diagnoses or therapeutic agents for ccRCC.


Assuntos
Carcinoma de Células Renais/genética , DNA Helicases/fisiologia , Proteínas de Ligação a DNA/fisiologia , Neoplasias Renais/genética , MicroRNAs/fisiologia , Proteínas de Ligação a Poli-ADP-Ribose/fisiologia , RNA Helicases/fisiologia , Proteínas com Motivo de Reconhecimento de RNA/fisiologia , RNA Longo não Codificante , Humanos , Células Tumorais Cultivadas
17.
Inflamm Res ; 71(2): 255-266, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35064304

RESUMO

BACKGROUND: The role of estrogen receptor ß (ERß) in the pathogenesis and development of breast cancer (BC) is controversial, and it is currently considered to play contradictory roles in different phenotypes. ERß2 is thought to promote the BC process, but its role in triple-negative breast cancer (TNBC) has not been reported. METHODS: In this study, we collected tumor tissues from 15 patients with TNBC and obtained a variety of TNBC cell lines as research objects. The plasmid vectors and RNA interference techniques were used to change the level of target genes in cells, quantitative PCR and Western Blots were used to detect gene expression levels, CCK-8 and EdU assay were used to detect cell growth, and Transwell was used to detect cell migration and invasion. Dual-luciferase gene reports and RNA immunoprecipitation (RIP) were used to verify gene targeting relationships. RESULTS: ERß2 was up-regulated in TNBC tissues and promoted the growth, migration, and invasion of TNBC cells. ERß2 regulated hsa_circ_0000732 expression by binding to SCARF1 promoter. Knockdown of hsa_circ_0000732 inhibited TNBC cell proliferation, migration, and invasion by upregulating miR-1184. CONCLUSION: Our present study found that ERß2 is upregulated in some TNBC cells and promotes TNBC cell growth, migration and invasion by regulating hsa_circ_0000732 targeting miR-1184. The special role of ERß2 in TNBC may be the breakthrough of a targeted treatment strategy for TNBC.


Assuntos
Receptor beta de Estrogênio/fisiologia , MicroRNAs/fisiologia , RNA Circular/fisiologia , Neoplasias de Mama Triplo Negativas/etiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Invasividade Neoplásica , Regiões Promotoras Genéticas , Receptores Depuradores Classe F/genética , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima
18.
Inflamm Res ; 71(2): 205-214, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35064305

RESUMO

OBJECTIVE: This study aimed to investigate the relationship between miR-21 and lipopolysaccharide (LPS)-induced myocardial injury and its molecular and regulatory mechanisms. METHODS: We constructed LPS-mediated myocardial injury model using C57BL/6J mice and H9c2 cells. In-vivo, in-vitro, RIP and dual-luciferase reporter assays were used to determine the effect of miR-21 on myocardial injury. RESULTS: In-vivo and in-vitro results showed that the expression of miR-21 was increased in LPS-treated H9c2 cells and myocardial tissues of mice, and the pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNF-α) and NF-κB pathway were activated in LPS-treated H9c2 cells. Besides, the B-cell lymphoma-2 (Bcl-2) and cyclin-dependent kinase 6 (CDK6) expression levels decreased, while Bax and cleaved caspase 9 levels increased in LPS-treated H9c2 cells. Inhibition of miR-21 could suppress LPS-induced apoptosis, inflammatory reactions and NF-κB activation to attenuate LPS-induced myocardial injury in H9c2 cells, and effectively improve survival of mice with sepsis. Most importantly, Bcl-2 and CDK6 were found to be the direct target of miR-21 using dual-luciferase reporter and RNA immunoprecipitation assays. Further gain-of-function assay demonstrated that Bcl-2 or CDK6 over-expression promoted the protective effects of miR-21 inhibitor on LPS-mediated myocardial cells. CONCLUSION: Our findings revealed that the down-regulation or antagonism of miR-21 protects myocardial cells against LPS-induced apoptosis and inflammation through up-regulating Bcl-2 and CDK6 expression, which provided a new insight for prevention and treatment of myocardial injury.


Assuntos
Quinase 6 Dependente de Ciclina/genética , Coração/efeitos dos fármacos , MicroRNAs/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Coração/fisiologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , NF-kappa B/fisiologia
19.
J Am Soc Nephrol ; 33(3): 565-582, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35091451

RESUMO

BACKGROUND: Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. METHODS: We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. RESULTS: After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. CONCLUSIONS: These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Integrina alfa5/metabolismo , MicroRNAs/fisiologia , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor TIE-2/fisiologia , Transdução de Sinais/fisiologia
20.
Clin Transl Oncol ; 24(3): 546-555, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35031966

RESUMO

OBJECTIVE: Accumulating evidence has been revealed that miR-590 is involved in the progression and carcinogenesis of various cancers. However, the molecular mechanism of miR-590 in non-small-cell lung cancer (NSCLC) remains unclear. METHODS: Quantitative reverse transcription-PCR (qRT-PCR), western blot, MTT, and transwell assay were applied to investigate the functional role of miR-590 in this study. Dual luciferase reporter assay was utilized to investigate the interaction between YAP1 and miR-590 expression. Cells transfected with miR-590 mimic or inhibitor were subjected to western blot to investigate the role of Wnt/ß-catenin signaling in NSCLC modulated by miR-590. RESULTS: MiR-590 was down-regulated in NSCLC tissues and cells. Kaplan-Meier analysis found that the higher expression of miR-590 in NSCLC patients, the more improved survival rate of NSCLC patients. Over-expression of miR-590 inhibited NSCLC cell proliferation, migration, and invasion. Moreover, increasing miR-590 suppressed Yes-associated protein 1 (YAP1) expression and inhibited the Wnt/ß-catenin pathway in NSCLC cells. Furthermore, miR-590 was negatively correlated with YAP1 expression. CONCLUSION: These findings demonstrated that the miR-590/YAP1 axis exerted an important role in the progression of NSCLC, suggesting that miR-590 might be the appealing prognostic marker for NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Via de Sinalização Wnt/fisiologia , /fisiologia , Progressão da Doença , Humanos , Células Tumorais Cultivadas
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