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In our work, a new-type, to the best of our knowledge, ferromagnetic insulator and its nonlinear optical absorption characteristics and related ultrafast modulation applications were investigated. Cr2Si2Te6 saturable absorbers (SAs) with a modulation depth and a saturable intensity of 9.7% and 3.5MW/cm2 were fabricated. By adjusting the pump power to 120 mW and optimizing the polarization state, traditional soliton operations were obtained successfully; the corresponding duration of pulse and the fundamental repetition rate were â¼1.33ps and 6.70 MHz, and the signal-to-noise ratio was 50 dB. The experimental results reveal that Cr2Si2Te6 with excellent saturable absorption characteristics can be used as a SA to obtain ultrafast pulse lasers.
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BACKGROUND: CircRNA has emerged as a new non-coding RNA that plays crucial roles in tumour initiation and development. 'MiRNA sponge' is the most reported role played by circRNAs in many tumours. The AKT/mTOR axis is a classic signalling pathway in cancers that sustains energy homeostasis through energy production activities, such as the Warburg effect, and blocks catabolic activities, such as autophagy. Additionally, the AKT/mTOR axis exerts a positive effect on EMT, which promotes tumour metastasis. METHODS: We detected higher circNRIP1 expression in gastric cancer by performing RNA-seq analysis. We verified the tumour promotor role of circNRIP1 in gastric cancer cells through a series of biological function assays. We then used a pull-down assay and dual-luciferase reporter assay to identify the downstream miR-149-5p of circNRIP1. Western blot analysis and immunofluorescence assays were performed to demonstrate that the circNRIP1-miR-149-5p-AKT1/mTOR axis is responsible for the altered metabolism in GC cells and promotes GC development. We then adopted a co-culture system to trace circNRIP1 transmission via exosomal communication and RIP experiments to determine that quaking regulates circNRIP1 expression. Finally, we confirmed the tumour suppressor role of microRNA-133a-3p in vivo in PDX mouse models. RESULTS: We discovered that knockdown of circNRIP1 successfully blocked proliferation, migration, invasion and the expression level of AKT1 in GC cells. MiR-149-5p inhibition phenocopied the overexpression of circNRIP1 in GC cells, and overexpression of miR-149-5p blocked the malignant behaviours of circNRIP1. Moreover, it was proven that circNRIP1 can be transmitted by exosomal communication between GC cells, and exosomal circNRIP1 promoted tumour metastasis in vivo. We also demonstrated that quaking can promote circNRIP1 transcription. In the final step, the tumour promotor role of circNRIP1 was verified in PDX models. CONCLUSIONS: We proved that circNRIP1 sponges miR-149-5p to affect the expression level of AKT1 and eventually acts as a tumour promotor in GC.
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Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN/genética , Neoplasias Gástricas/genética , Serina-Treonina Quinasas TOR/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Exosomas/metabolismo , Exosomas/patología , Femenino , Xenoinjertos , Humanos , Metástasis Linfática , Masculino , Ratones , MicroARNs/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN/antagonistas & inhibidores , ARN/metabolismo , ARN Circular , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Trefoil Factor 1 (TFF1, also named pS2), which serves as the gastrointestinal mucosal protector, is known as gastric-specific tumor suppressor gene. However, the genetic variants of TFF1 are still not well studied. In our study, we aim to explore the effects of tagging single nucleotide polymorphisms (tagSNPs) of TFF1 on risk and prognosis of gastric cancer. Seven tagSNPs of TFF1 gene were first analyzed in the discovery set, which was consisted of 753 cases and 950 cancer-free controls. Then, the validation set (940 cases and 1,042 controls) was used for further evaluation. Moreover, we also tested the relation between these tagSNPs and prognosis of gastric cancer (GC). A series of experiments were performed to investigate the underlying mechanisms. We found that rs3761376 AA in the promoter region of TFF1, could reduce the expression of TFF1 by affecting the binding affinity of estrogen receptor 1 (ESR1, ERα), and thereby increased the risk of GC (1.29, 1.08-1.53). Moreover, the rs3761376 AA genotype was also found associated with worse prognosis among patients receiving 5-FU based chemotherapy after surgery (1.71, 1.18-2.48). Further functional assays demonstrated that TFF1 could increase the chemosensitivity of 5-FU by modulating NF-κB targeted genes. These results identified the effect of rs3761376 on TFF1 expression, which accounted for the correlation with susceptibility and prognosis of GC; and this genetic variant may be a potential biomarker to predict the risk and survival of GC.
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Neoplasias Gástricas/genética , Factor Trefoil-1/genética , Anciano , Estudios de Casos y Controles , Receptor alfa de Estrógeno/biosíntesis , Receptor alfa de Estrógeno/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Pronóstico , Regiones Promotoras Genéticas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factor Trefoil-1/biosíntesisRESUMEN
BACKGROUND/AIMS: There is little published data on the role of FOXP3 in gastric cancer. METHODS: FOXP3 expression and localization in gastric cancer tissues and cells were examined by immunohistochemistry, RT-PCR, flow cytometry, western blot, and laser confocal microscopy. CCK8, plate clone, wound healing, and transwell insert assays were performed for gastric cancer cells. Potential molecules and signaling pathways were screened using high-throughput transcriptome sequencing. RESULTS: FOXP3 expression in gastric cancer tissues was higher than that in para-carcinoma tissues. It was restricted to the cytoplasm of para-carcinoma tissues, but was observed in the cytoplasm or/and nuclei of gastric cancer tissues. FOXP3 expression was positively correlated with pathological grading, and was detected in gastric cancer and GES-1 cells, where it was expressed in the cytoplasm alone, or in both the cytoplasm and the nucleus. FOXP3 overexpression promoted cell proliferation, migration, and invasion, while FOXP3 knockdown suppressed these effects. Furthermore, RT-PCR and ELISA confirmed that FOXP3 upregulation resulted in increased TGF-ß expression and secretion in gastric cancer cells. CONCLUSION: FOXP3 expression was associated with degree of gastric cancer differentiation. In addition, upregulated and ectopic tumoral FOXP3 can promote gastric cancer proliferation, migration, and invasion, partly through the TGF-ß pathway.
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Factores de Transcripción Forkhead/metabolismo , Neoplasias Gástricas/patología , Anciano , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Femenino , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias Gástricas/metabolismo , Factor de Crecimiento Transformador beta/análisis , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND/AIMS: Dysregulation of microRNAs is correlated with tumor development. The aim of this study is to investigate the clinicopathologic and prognostic significance of microRNA (miR)-409-3p and its tumor suppressor roles in lung adenocarcinoma (LAD). METHODS: Quantitative real-time PCR (qRT-PCR) was performed to detect miR-409-3p expression in LAD tissues and corresponding noncancerous tissues. Additionally, the correlations of miR-409-3p expression with clinicopathologic factors and prognosis of patients were statistically analyzed. Next, we investigated whether miR-409-3p could function as a tumor suppressor in LAD cells via regulation of Akt signaling by targeting receptor tyrosine kinase (c-Met). RESULTS: MiR-409-3p was significantly downregulated in LAD tissues compared with corresponding noncancerous tissues. Low miR-409-3p expression was observed to be significantly correlated with poorer tumor differentiation, advanced pTNM stage and higher incidence of lymph node metastasis. Multivariate Cox regression analyses showed that miR-409-3p expression was an independent prognostic factor for LAD patients. Functional analyses indicated that miR-409-3p could inhibit growth, induce apoptosis, reduce migration and invasion in LAD cells via inactivation of Akt signaling by targeting c-Met. CONCLUSIONS: MiR-409-3p was an independent prognostic factor and functioned as a tumor suppressor in LAD via regulation of Akt signaling by targeting c-Met.
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Adenocarcinoma/genética , Genes Supresores de Tumor/fisiología , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-met/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Apoptosis/genética , Diferenciación Celular/genética , Línea Celular , Línea Celular Tumoral , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática/genética , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genéticaRESUMEN
Intraoperative hemorrhage is an important factor affecting intraoperative safety and postoperative patient recovery in percutaneous nephrolithotomy (PCNL). This study aimed to identify the factors that influence intraoperative hemorrhage during PCNL and develop a predictive nomogram model based on these factors.A total of 118 patients who underwent PCNL at the Department of Urology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University from January 2021 to September 2023 was included in this study. The patients were divided into a hemorrhage group (58 cases) and a control group (60 cases) based on the decrease in hemoglobin levels after surgery. The clinical data of all patients were collected, and both univariate analysis and multivariate logistic regression analysis were conducted to identify the independent risk factors for intraoperative hemorrhage during PCNL. The independent risk factors were used to construct a nomogram model using R software. Additionally, receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA) were utilized to evaluate the model.Multivariate logistic regression analysis revealed that diabetes, long operation time and low psoas muscle mass index (PMI) were independent risk factors for intraoperative hemorrhage during PCNL (P < 0.05). A nomogram model was developed incorporating these factors, and the areas under the ROC curve (AUCs) in the training set and validation set were 0.740 (95% CI: 0.637-0.843) and 0.742 (95% CI: 0.554-0.931), respectively. The calibration curve and Hosmer-Lemeshow test (P = 0.719) of the model proved that the model was well fitted and calibrated. The results of the DCA showed that the model had high value for clinical application.Diabetes, long operation time and low PMI were found to be independent risk factors for intraoperative hemorrhage during PCNL. The nomogram model based on these factors can be used to predict the risk of intraoperative hemorrhage, which is beneficial for perioperative intervention in high-risk groups to improve the safety of surgery and reduce the incidence of postoperative complications.
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Pérdida de Sangre Quirúrgica , Nefrolitotomía Percutánea , Nomogramas , Humanos , Nefrolitotomía Percutánea/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Adulto , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Cálculos Renales/cirugía , Tempo Operativo , Estudios Retrospectivos , Curva ROC , Complicaciones Intraoperatorias/etiología , Complicaciones Intraoperatorias/epidemiología , AncianoRESUMEN
BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. METHODS: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. RESULTS: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo. CONCLUSIONS: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.
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Proteína Glutamina Gamma Glutamiltransferasa 2 , Factor de Transcripción STAT1 , Neoplasias Gástricas , Humanos , Calcimicina , Línea Celular Tumoral , Guanosina Trifosfato/metabolismo , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Neoplasias Gástricas/patología , UbiquitinaciónRESUMEN
Background: Colorectal cancer (CRC) is the third most common cancer worldwide and one of the leading causes of cancer-related death. Peptidomics, considered a novel branch of proteomics, has an increasing range of applications in the screening, diagnosis, prognosis, and even monitoring of cancer. However, there is little information for peptidomics analysis in CRC. Methods: In this study, a comparative peptidomic profiling was analyzed in 3 CRC tissue samples and 3 adjacent intestinal epithelial tissue samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Among the total 133 nonredundant peptides identified, 59 were significantly differentially expressed in the CRC samples and benign colonic epithelium conditions [fold change (FC) >2, P<0.05]. Totals of 25 up-regulated and 34 down-regulated peptides were detected, respectively. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to predict the possible functions of these relevant precursor proteins. To clearly identify the potential interaction network of peptide precursors, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to determine protein interactions and a possible central role in CRC. Conclusions: Our results for the first time revealed the differentially expressed peptides between the serous CRC tissue and the adjacent intestinal epithelial tissue samples, and these prominently variable peptides might have an important potential role in occurrence and development of CRC.
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Background: Recently, the use of immunochemotherapy in the treatment of advanced gastric cancer (GC) has been increasing and programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy has become the first-line treatment for advanced GC. However, few studies with small sample sizes have examined this treatment regimen to assess its effectiveness and safety in the neoadjuvant treatment phase of resectable local advanced GC. Materials and methods: Herein, we systematically searched PubMed, Cochrane CENTRAL, and Web of Science for clinical trials on neoadjuvant immunochemotherapy (nICT) in advanced GC. The primary outcomes were effectiveness [evaluated by major pathological response (MPR) and pathological complete response (pCR)] and safety [assessed by grade 3-4 treatment-related adverse events (TRAEs) and postoperative complications]. A meta-analysis of non-comparative binary results was performed to aggregate the primary outcomes. Direct comparative analysis was used to compare pooled results of neoadjuvant chemotherapy (nCT) with nICT. The outcomes emerged as risk ratios (RR). Results: Five articles with 206 patients were included, and all of them were from the Chinese population. The pooled pCR and MPR rates were 26.5% (95% CI: 21.3%-33.3%) and 49.0% (95% CI: 42.3%-55.9%), while grade 3-4 TRAEs and post-operative complication rates were 20.0% (95% CI: 9.1%-39.8%) and 30.1% (95% CI: 23.1%-37.9%), respectively. Direct comparison showed that with the exception of grade 3-4 TRAEs and postoperative complications, all outcomes including pCR, MPR, and R0 resection rate favoured nICT to nCT. Conclusion: nICT is a promising strategy for use as an advisable neoadjuvant treatment for patients with advanced GC in Chinese population. However, more phase III randomized controlled trials (RCTs) will be required to further consolidate the efficacy and safety of this regimen.
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Inmunoterapia , Terapia Neoadyuvante , Neoplasias Gástricas , Humanos , Pueblos del Este de Asia , Proyectos Piloto , Complicaciones Posoperatorias , Neoplasias Gástricas/terapiaRESUMEN
BACKGROUND: Chemotherapy can significantly improve the disease-free survival and overall survival of patients with advanced gastric cancer (GC). 5-fluorouracil (5-FU) is frequently applied in the clinic, acting as a first-line chemotherapy drug of advanced GC, which could be used alone or combining platinum drugs. However, its efficacy is significantly attenuated by chemoresistance, which is associated with patients' poor survival. Recently, there is evidence suggesting that dysregulation of autophagy may contribute to drug resistance in cancer, and circular RNAs (circRNAs) also take part in chemoresistance. However, whether circRNAs participate in 5-FU chemoresistance through autophagy remains largely unknown. METHODS: RNA sequencing technologies and bioinformatics analysis were performed in GC. Sanger sequencing, Actinomycin D assay and RNase R assay confirmed the circular structure of circular CPM (circCPM). Various cell line models and animal models were used to explore related functions in vitro and in vivo. Quantitative Real-time PCR (qRT-PCR), fluorescence in situ hybridization, ribonucleic acid; (RNA) pulldown assays, RNA binding protein immunoprecipitation assays and Luciferase reporter assays were applied to explore involved pathways. RESULTS: circCPM was up-regulated in 5-FU resistant GC cell lines and tissue. Moreover, high circCPM expression is positively associated with poor survival. Silencing circCPM greatly improved chemosensitivity in vitro and in vivo. Mechanistically, it directly binds to miR-21-3p in the cytoplasm and therefore increases the expression of PRKAA2, contributing to the activation of autophagy and chemoresistance. CONCLUSION: Our results reveal that circCPM has a crucial role in regulating GC autophagy and 5-FU resistance by targeting PRKAA2. It may function as a new theory basis for assessing the curative effect of GC and reversing 5-FU chemoresistance.
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Proteínas Quinasas Activadas por AMP/metabolismo , Neoplasias Gástricas/genética , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/farmacología , Autofagia/genética , Proteínas Ligadas a GPI/agonistas , Proteínas Ligadas a GPI/metabolismo , Humanos , Estimación de Kaplan-Meier , Metaloendopeptidasas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , MicroARNs/uso terapéuticoRESUMEN
[This retracts the article DOI: 10.1016/j.omtn.2017.10.008.].
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Recently, a novel modified smoothed finite element method (M-SFEM) is proposed to calculate the band structures of two-dimensional (2D) in-plane elastic waves in phononic crystals (PCs) by the authors. In present work, the proposed algorithm is extended to analyze the band structures of 2D phononic crystals (PCs) with fluid/structure interaction (FSI). In order to study the phononic crystals (PCs) with FSI, this method extends the gradient smoothing technique to soften the stiffness matrix of fluid domain and solid domain. Meanwhile, according to the generalized integration rules, this method simply shifts these integration points of elements to an unconventional location in the mass matrix. In addition, different Bloch boundary conditions, viz. fluid/solid and solid/fluid, including the square and triangular lattice using M-SFEM are also investigated in the computation of PCs with FSI. Several PCs models with FSI are studied to verify the high accuracy of the M-SFEM in the analysis of band structures. In order to emerge the superiority of the proposed method, the results of finite element method (integration points on conventional location), modified finite element method (integration points on unconventional location), smoothed finite element method are all presented. Numerical analysis shows that the M-SFEM can be used to predict the band structures in PCs with FSI, and can obtained more precise results as compared to FEM and SFEM.
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AIMS: To explore the effect on food allergy of stachyose. MAIN METHODS: The egg allergen ovalbumin (OVA) was used to induce a food allergy model of BALB/c mice, and different doses of stachyose were given in process. Using enzyme-linked immunosorbent assay (ELISA) methods to detect the levels of IgE, IgG1, histamine and cytokines. And flow cytometry was used to analyze TH1/TH2 balance further. Besides, Hematoxylin-eosin (HE) staining was used to observe changes of intestinal morphology. Lastly, Reverse Transcription-Polymerase Chain Reaction (RT-qPCR) and western Blot was conducted to explore the possible mechanism. KEY FINDINGS: Compared with OVA group, serum IgE and IgG1 levels in the low-dose (1mg/mouse) group and high-dose (5mg/mouse) group of stachyose were significantly reduced (P < 0.05); the level of plasma histamine was also decreased significantly (P < 0.05) and the body temperature were decreased. In all, allergic symptoms were alleviated after stachyose treatment. Furthermore, TH1/TH2 balance was improved after stachyose treatment. Lastly, the expression of TLR2 and NF-κB were increased significantly (P < 0.05) in both mRNA and protein levels after stachyose treatment. SIGNIFICANCE: Food allergy was alleviated through improving TH1/TH2 balance by activating TLR2/NF-κB signal by stachyose.
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Hipersensibilidad a los Alimentos/tratamiento farmacológico , Oligosacáridos/farmacología , Alérgenos/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad a los Alimentos/metabolismo , Histamina/metabolismo , Inmunoglobulina E/sangre , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Oligosacáridos/metabolismo , Ovalbúmina/inmunología , Ovalbúmina/metabolismo , Transducción de Señal/efectos de los fármacos , Células TH1/inmunología , Células Th2/inmunología , Receptor Toll-Like 2/metabolismoRESUMEN
BACKGROUND: Previous studies have confirmed the antitumor effects of cimetidine, while the therapeutic targets and the mechanisms are not yet fully understood. We previously reported the protumoral role of endogenous FOXP3 in gastric cancer (GC), but whether cimetidine plays an antitumor role by targeting FOXP3 is still unknown. METHODS: A series of assays were used to examine the role of cimetidine on the malignant behaviors and the expression of endogenous FOXP3 in GC cells. The role of cimetidine on ligase E3-STUB1and the role of STUB1 on FOXP3 level were examined, with the signaling pathway involved in these processes also being explored. RESULTS: Cimetidine inhibited the malignant behaviors of GC cells, and led to the ubiquitination/degradation of FOXP3. Moreover, cimetidine promoted STUB1 expression, STUB1 knockdown rescued the decline of FOXP3 in cimetidine-treated GC cells, and reduced the turnover effect of cimetidine on GC cells, but had minimal effect in untreated cells. Immunoprecipitation (IP) assay confirmed the formation of the STUB1-FOXP3 complex in cimetidine-treated GC cells. Furthermore, Cimetidine promoted STUB1 expression by activating PI3K/Akt pathway, and the inhibition of PI3K/Akt pathway rescued the decline of FOXP3 by suppressing the upregulation of STUB1. CONCLUSIONS: Cimetidine suppressed GC development by promoting STUB1-mediated ubiquitination/degradation of endogenous FOXP3 through the activation of the PI3K/Akt pathway.
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Neural invasion (NI) is one of the important routes for local spread of gastric cancer (GC) correlated with poor prognosis. However, the exact cellular characteristics and molecular mechanisms of NI in GC are still unclear. Netrin-1(NTN1) as an axon guidance molecule was firstly found during neural system development. Importantly, NTN1 has an essential role in the progression of malignant tumor and specifically mediates the induction of invasion. In this study, we found NTN1 expression was significantly increased in 97 tumor tissues from GC patients and positively correlated with NI (p<0.05). In addition, we detected NTN1 knockdown significantly suppressed GC cells migration and invasion. Moreover, our results showed that reciprocity was observed between GC cells and neurites colonies in dorsal root ganglia (DRG)-GC cells co-culture vitro model. GC cells with NTN1 silencing could suppress their abilities to navigate along surrounding neuritis and this effect was depended on its receptor neogenin. In vivo, NTN1 inhibition also decreased GC cells sciatic nerve invasion. Taken together, our findings argue that NTN1 and its receptor neogenin might act synergistically in promoting GC cells neural invasion. Inhibiting the activity of NTN1 could be a potential strategy targeting NI in GC therapy.
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OBJECTIVES: Gastric cancer (GC) is one of the most common cancers in the world, causing a large number of deaths every year. The Slit-Robo signalling pathway, initially discovered for its critical role in neuronal guidance, has recently been shown to modulate tumour invasion and metastasis in several human cancers. However, the role of Slit-Robo signalling and the molecular mechanisms underlying its role in the pathogenesis of gastric cancer remains to be elucidated. MATERIALS AND METHODS: Slit2, Robo1 and USP33 expressions were analysed in datasets obtained from the Oncomine database and measured in human gastric cancer specimens. The function of Slit2-Robo1-USP33 signalling on gastric cancer cells migration and epithelial-mesenchymal transition (EMT) was studied both in vitro and in vivo. The mechanism of the interaction between Robo1 and USP33 was explored by co-IP and ubiquitination protein analysis. RESULTS: The mRNA and protein levels of Slit2 and Robo1 are lower in GC tissues relative to those in adjacent healthy tissues. Importantly, Slit2 inhibits GC cell migration and suppresses EMT process in a Robo-dependent manner. The inhibitory function of Slit2-Robo1 is mediated by ubiquitin-specific protease 33 (USP33) via deubiquitinating and stabilizing Robo1. USP33 expression is decreased in GC tissues, and reduced USP33 level is correlated with poor patient survival. CONCLUSIONS: Our study reveals the inhibitory function of Slit-Robo signalling in GC and uncovers a role of USP33 in suppressing cancer cell migration and EMT by enhancing Slit2-Robo1 signalling. USP33 represents a feasible choice as a prognostic biomarker for GC.
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Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Inmunológicos/metabolismo , Neoplasias Gástricas/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Anciano , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/genética , Pronóstico , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Receptores Inmunológicos/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/genética , Ubiquitinación , Proteínas RoundaboutRESUMEN
OBJECTIVES: It has been accounted that miR-664a-3p has different functions in several malignancies; however, the precise role and underlying mechanism in gastric cancer have not been elucidated. Our study aims to explore the function of miR-664a-3p on the progression of gastric cancer (GC). METHODS: qRT-PCR was applied to detect the expression of miR-664a-3p in GC tissues and cells. The functions of miR-664a-3p on GC in vitro were examined by cell proliferation assay, and transwell assay. Related proteins of epithelial-mesenchymal transition (EMT) and signal pathway were evaluated by Western blot and immunofluorescence analysis. The bioinformatic, dual-luciferase assay or ChIP assay were employed to identify the interaction between miR-664a-3p and its target gene or Foxp3. The effects in vivo were investigated through a mouse tumorigenicity model. RESULTS: miR-664a-3p was frequently upregulated in GC tissues and cells. Elevated expression of miR-664a-3p significantly promoted proliferation and invasion in vitro and in vivo. MOB1A was confirmed to be a target of miR-664a-3p and restoration of MOB1A attenuated the effects of miR-664a-3p. A series of investigations indicated that miR-664a-3p contributed to EMT process and inactivated the Hippo pathway by downregulating MOB1A. CONCLUSION: Taken together, we revealed that miR-664a-3p functions as an oncogene by targeting Hippo pathway in the development of gastric cancer.
Asunto(s)
MicroARNs/genética , Oncogenes , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Xenoinjertos , Vía de Señalización Hippo , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica/genética , Transducción de Señal , Neoplasias Gástricas/patología , Regulación hacia ArribaRESUMEN
Imatinib is a first-line drug for the treatment of gastrointestinal stromal tumors (GIST). This study aims to investigate the influence of different kinds of protein concentrations and genetic polymorphisms of metabolizing enzymes and drug transporters on unbound imatinib and its active metabolite N-desmethyl-imatinib concentration, as well as the relationship between adverse drug reactions (ADRs) and drug concentration. A total of 62 Chinese patients with GIST were genotyped for five single nucleotide polymorphisms (SNPs). Total and unbound 3h and trough concentration of imatinib and N-desmethyl-imatinib in GIST patients were determined by an LC-MS/MS method combined with an equilibrium dialysis. Single-Use Red Plate with inserts was used to separate the unbound drug. When the protein concentration became higher, the unbound imatinib and N-desmethyl-imatinib plasma concentration got higher (p < 0.05). Patients with GA genotype in rs755828176 had significantly higher unbound N-desmethyl-imatinib dose-adjusted trough plasma concentrations (p = 0.012). Patients with CC genotype in rs3814055 had significantly higher unbound imatinib dose-adjusted trough plasma concentrations (p = 0.040). The mean total imatinib C3h of patients with ADRs (3.10 ± 0.96 µg/ml) was significantly higher than that of patients without ADRs (p = 0.023). The mean total N-desmethyl-imatinib C3h of patients (0.64 ± 0.21 µg/ml) with ADRs was significantly higher than that of patients without ADRs (p = 0.004). The mean unbound N-desmethyl-imatinib C3h of patients with ADRs (6.49 ± 2.53 ng/ml) was significantly higher than that of patients without ADRs (p = 0.042). The total and unbound C3h of imatinib and N-desmethyl-imatinib in patients with ADRs was significantly higher than that in patients without ADRs (p < 0.05). Protein concentrations have great influence on the unbound imatinib and N-desmethyl-imatinib concentrations. The genetic polymorphisms of CYP3A4 rs755828176 and NR1I2 rs3814055 were significantly associated with unbound imatinib and N-desmethyl-imatinib dose-adjusted trough plasma levels. The total and unbound imatinib or N-desmethyl-imatinib concentration in patients with GIST was also significantly correlated with ADRs.
RESUMEN
Increasing evidence indicates that microRNAs (miRNAs) play an important role in various tumors by regulating downstream target genes and diverse signaling pathways. Herein, we confirmed miR-1265 expression in gastric cancer (GC) using the Cancer Genome Atlas (TCGA) database and assessed the level of miR-1265 expression in clinical specimens and cell lines. We found that miR-1265 expression was negatively correlated with tumor size. Further functional analysis revealed that miR-1265 suppresses cellular proliferation and autophagy while inducing apoptosis in GC cells. A luciferase reporter assay was used to identify an miR-1265 targeted gene, calcium binding protein 39 (CAB39), which is an essential upstream regulator in the AMPK-mTOR signaling pathway. Upregulation or downregulation of CAB39 expression reversed the effects of miR-1265 overexpression or inhibition, respectively. Notably, the knockdown of autophagy-related gene 12 (ATG12) impaired the effects of miR-1265 inhibition or CAB39 overexpression in GC. MiR-1265 also suppressed the growth of GC cells in vivo and that of human gastric organoids. Altogether, our results show that miR-1265 suppresses GC progression and oncogenic autophagy by reducing CAB39 expression and regulating the AMPK-mTOR signaling pathway. Therefore, miR-1265 may represent a potential therapeutic target for GC.