RESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a serious malignant cancer. The treatment effect of ESCC is relatively poor and needs further improvement. According to reports, circular RNAs (circRNAs) actively participate in human carcinogenesis. More explorations are needed about the action of circRNAs in ESCC. METHODS: Circ_0024108, miR-488-3p, and USP14 was quantified by a qRT-PCR or immunoblotting method. Cell proliferation evaluation was performed by MTT, EdU, and colony formation assays. Evaluation of cell motility and invasiveness was conducted using wound healing assay and transwell assay. The regulatory mechanism of circ_0024108, miR-488-3p, and USP14 was detected by RNA pull-down assay and dual-luciferase reporter assay. RESULTS: Circ_0024108 and USP14 were significantly overexpressed in ESCC, while miR-488-3p was underexpressed. Deficiency of circ_0024108 impeded cell growth, motility, and invasiveness. Circ_0024108 regulated the expression of USP14 in ESCC cells via miR-488-3p. Also, circ_0024108 was present at high levels in serum exosomes from ESCC patients with high specificity and sensitivity. CONCLUSIONS: Taken together, circ_0024108 participated in the progress of ESCC through the miR-488-3p/USP14 axis. Circ_0024108 was differentially expressed in serum exosomes. Circ_0024108 might be a potential biomarker for the diagnosis of ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Humanos , Neoplasias Esofágicas/genética , RNA Circular/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proliferação de Células , MicroRNAs/genética , Ubiquitina TiolesteraseRESUMO
Metformin (Metf), a biguanide widely used to manage type 2 diabetes mellitus, has recently entered the spotlight as a hopeful anti-tumor agent. In this work, because of the hyaluronic acid (HA) capability to specifically target CD44 receptors over-expressed on the surface of non-small lung cancer cells, a tumor-targeted drug delivery nanocarrier-based HA-coated mesoporous silica nanoparticles (MSNs) have been used for active targeting and efficient delivery of Metf. For this purpose, the synthesized MSNs-HA were characterized using BET, FE-EM, DLS, and FTIR. Confocal microscopy was applied to show the enhanced cellular uptake of the FITC-labelled MSNs-HA compared to MSNs without HA coating. MTT and qPCR results also revealed superior cytotoxicity and pro-apoptotic effects of Metf-loaded MSNs-HA (Metf@MSNs-HA) against the A549 lung cancer cells compared to the free Metf and MSNs@Metf due to the efficient CD44-targeting capability and delivery of Metf@MSNs-HA. Besides, it was demonstrated that Metf@MSNs-HA could effectively trigger the AMP-activated protein kinase α (AMPKα) pathway and inhibit the mammalian target rapamycin (mTOR), increasing the growth suppression. In conclusion, this preliminary work disclosed the great potential of Metf@MSNs-HA in targeted therapy of lung cancer cells.
Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias Pulmonares , Metformina , Nanopartículas , Humanos , Ácido Hialurônico , Doxorrubicina/farmacologia , Dióxido de Silício , Metformina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , PorosidadeRESUMO
Although cisplatin (DDP)-based therapy is the most predominant chemotherapeutic strategy used for lung cancer, drug resistance usually occurs after several cycle use of it. Circular RNAs (circRNAs) are found to be involved in the chemoresistance in lung cancer. Hence, this study aimed to clarify the role and mechanism of circ_0048856 in lung cancer tumorigenesis and DDP resistance. The levels of circ_0048856, miR-193a-5p, miR-98-5p and ABCC1 (ATP Binding Cassette Subfamily C Member 1) were determined by qRT-PCR and western blotting. In vitro assays were conducted by cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EDU) assay, flow cytometry and transwell assay, respectively. The binding interaction was verified using dual-luciferase reporter assay and RIP assay. In vivo experiment was performed by the establishment of murine xenograft model. Circ_0048856 was highly expressed in DDP-resistant lung cancer tissues and cells. Functionally, circ_0048856 silencing re-sensitized DDP-resistant lung cancer cells to DDP, as well as suppressed cell growth and invasion in lung cancer in vitro and in vivo. Mechanistically, circ_0048856 acted as the sponge for miR-193a-5p or miR-98-5p, which targeted ABCC1. Furthermore, rescue experiments showed that inhibition of miR-193a-5p or miR-98-5p reversed the effects of circ_0048856 knockdown on lung cancer cells. Besides that, overexpression of miR-193a-5p or miR-98-5p suppressed cell tumorigenesis and reduced DDP resistance in lung cancer, which were attenuated by ABCC1 up-regulation. Circ_0048856 knockdown suppressed tumor growth and reduced DDP resistance in lung cancer by miR-193a-5p/ABCC1 or miR-98-5p/ABCC1 axis, indicating a novel strategy for efficient application of DDP in lung cancer.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Humanos , Animais , Camundongos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinogênese/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Sítios de Ligação , Proliferação de Células , MicroRNAs/genética , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
The protective effects of downregulated miR-199a-5p on ischemic and hypoxic cardiomyocytes were well recognized, but the underlying mechanism of inhibited miR-199a-5p is not yet clear. The present study explored the relationship between enhanced signal transducer and activator of transcription 3 (STAT3) signaling and lowered production of miR-199a-5p in hypoxic cardiomyocytes. This study firstly found the correlation between elevated interleukin (IL)-6 and IL-11, as well as subsequent STAT3 signaling activation and the downregulation of miR-199a-5p in hypoxic myocardial samples from children with congenital heart disease. Then, using model of hypoxic mice and the intervention of phosphorylated STAT3 (pSTAT3), it was observed that pSTAT3 affected the expression of miR-199a-5p and modulated the expression of its target genes, including endoplasmic reticulum stress (ERS)-related activating transcription factor 6 (ATF6) and 78 kDa glucose-regulated protein (GRP78). Further observation revealed that the pSTAT3 signal in cardiac tissue could affect the expression of pri-miR-199a-2, a precursor of miR-199a-5p. And the chromatin immunoprecipitation (ChIP) assay also confirmed that pSTAT3 could bind to the promoter region of miR-199a-2 gene, which is more significant under hypoxic conditions. In conclusion, the activation of STAT3 signaling in cardiomyocytes during chronic hypoxia leads to downregulation of miR-199a-5p, which promotes the expression of many downstream target genes. This is an important pathway in the adaptive protection mechanism of myocardium during hypoxia.
Assuntos
Fístula Arteriovenosa/genética , Cardiopatias Congênitas/genética , Hipóxia/genética , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Fator de Transcrição STAT3/genética , Tetralogia de Fallot/genética , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Adolescente , Animais , Fístula Arteriovenosa/metabolismo , Fístula Arteriovenosa/patologia , Fístula Arteriovenosa/cirurgia , Ponte Cardiopulmonar , Criança , Pré-Escolar , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Feminino , Regulação da Expressão Gênica , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/cirurgia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Interleucina-11/genética , Interleucina-11/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Regiões Promotoras Genéticas , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/cirurgia , Veias Pulmonares/metabolismo , Veias Pulmonares/patologia , Veias Pulmonares/cirurgia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Tetralogia de Fallot/metabolismo , Tetralogia de Fallot/patologia , Tetralogia de Fallot/cirurgia , Resposta a Proteínas não DobradasRESUMO
Transthoracic device closure (TTDC) is thought to be a promising technology for the repair of ventricular septal defects (VSDs). However, there is considerable controversy regarding the efficacy and safety of TTDC. The present study aimed to compare the benefits and safety of TTDC with those of conventional open-heart surgery (COHS) and analyze the associated factors causing complications, conversion to COHS and reoperation. Electronic database searches were conducted in PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov and several Chinese databases. A total of 5 randomized controlled trials (RCTs), 7 cohort studies, 13 case-control studies, 129 case series and 13 case reports were included. Compared to COHS, TTDC exhibited superior efficacy with a significantly lower risk of post-operative arrhythmia; however, no significant differences in other outcomes were identified. Meta-regression analysis showed that perimembranous VSDs (pmVSDs), a smaller VSD, a smaller occluder, and a median or subxiphoid approach lowered the relative risk of several post-operative complications, conversion to COHS and reoperation. The current evidence indicates that TTDC is associated with a lower risk of post-operative arrhythmia and is not associated with an increased risk of complications. PmVSDs, a smaller VSD and occluder, and a median or subxiphoid approach correlate with better outcomes when using TTDC.