RESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is marked by a dismal survival rate, lacking effective therapeutics due to its aggressive growth, late-stage diagnosis, and chemotherapy resistance. Despite debates on NF-κB targeting for PDAC treatment, no successful approach has emerged. METHODS: To elucidate the role of NF-κB, we ablated NF-κB essential modulator (NEMO), critical for conventional NF-κB signaling, in the pancreata of mice that develop precancerous lesions (KC mouse model). Secretagogue-induced pancreatitis by cerulein injections was utilized to promote inflammation and accelerate PDAC development. RESULTS: NEMO deletion reduced fibrosis and inflammation in young KC mice, resulting in fewer pancreatic intraepithelial neoplasias (PanINs) at later stages. Paradoxically, however, NEMO deletion accelerated the progression of these fewer PanINs to PDAC and reduced median lifespan. Further, analysis of tissue microarrays from human PDAC sections highlighted the correlation between reduced NEMO expression in neoplastic cells and poorer prognosis, supporting our observation in mice. Mechanistically, NEMO deletion impeded oncogene-induced senescence (OIS), which is normally active in low-grade PanINs. This blockage resulted in fewer senescence-associated secretory phenotype (SASP) factors, reducing inflammation. However, blocked OIS fostered replication stress and DNA damage accumulation which accelerated PanIN progression to PDAC. Finally, treatment with the DNA damage-inducing reagent etoposide resulted in elevated cell death in NEMO-ablated PDAC cells compared to their NEMO-competent counterparts, indicative of a synthetic lethality paradigm. CONCLUSIONS: NEMO exhibited both oncogenic and tumor-suppressive properties during PDAC development. Caution is suggested in therapeutic interventions targeting NF-κB, which may be detrimental during PanIN progression but beneficial post-PDAC development.
Assuntos
Carcinoma Ductal Pancreático , Progressão da Doença , NF-kappa B , Neoplasias Pancreáticas , Transdução de Sinais , Animais , Humanos , Camundongos , Carcinoma in Situ/patologia , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Knockout , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/etiologiaRESUMO
In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.
Assuntos
Sistema Hipotálamo-Hipofisário , Receptores de Glucocorticoides , Feminino , Gravidez , Animais , Camundongos , Sistema Hipotálamo-Hipofisário/metabolismo , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , HomeostaseRESUMO
Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.
Assuntos
Antineoplásicos , Produtos Biológicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/química , Produtos Biológicos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Descoberta de Drogas , Organismos Aquáticos/químicaRESUMO
BACKGROUND: The aim of this systematic review and meta-analysis was to introduce the relatively novel method of ultrasound-guided local lauromacrogol injection (USG-LLI) followed by dilatation and curettage for caesarean scar pregnancy (CSP) and to investigate the clinical safety and efficacy between uterine artery embolization (UAE) and USG-LLI in the treatment of CSP. METHODS: The relevant literature and articles about USG-LLI, UAE and CSP published in eight electronic databases were searched to extract the primary outcomes for the selected articles. Review Manager Software(RevMan) V.5.2 was used for quantitative data synthesis and data analysis. Forest plots, sensitivity analysis and bias analysis were also performed on the included articles. RESULTS: Of 10 studies included in our search, 623 patients were in the USG-LLI group and 627 patients were in the UAE groups. There were no significant differences between the two groups in terms of success rate, blood loss and time to human chorionic gonadotropin (hCG) normalization. However, USG-LLI group patients than UAE group patients had a shorter duration of hospital stay (mean difference [MD] = -1.97; 95% confidence intervals [CI] -2.63 to -1.31; P < 0.05; I2 = 95%), shorter restored menses (MD = -4.84; 95%CI -5.78 to -3.90; P < 0.05; I2 = 95%), and lower complication rates [odds ratio(OR) = 0.21; 95%CI:0.15 to 0.30; P < 0.05]; and cheaper on expenses of hospitalization (MD = -8028.29; 95%CI -10,311.18 to -5745.40; P < 0.05; I2 = 100%). CONCLUSIONS: The results demonstrate that USG-LLI is comparable in curative effect and success rates with UAE in the therapy of CSP, but patients in the USG-LLI group seem to have fewer complications rates, shorter duration of hospital stays and lower costs.
Assuntos
Cicatriz , Embolização da Artéria Uterina , Feminino , Gravidez , Humanos , Polidocanol , Cicatriz/etiologia , Cicatriz/terapia , Embolização da Artéria Uterina/efeitos adversos , Ultrassonografia de Intervenção , Cesárea/efeitos adversosRESUMO
Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.
Assuntos
Alcaloides , Produtos Biológicos , Corydalis , Benzofenantridinas/farmacologia , Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Linhagem Celular TumoralRESUMO
Background and Objectives: Most published research has only investigated a single timepoint after the onset of severe acute pancreatitis (SAP), meaning that they have been unable to observe the relationship between the dynamic changes in cytokines and SAP progression. In this study, we attempted to reveal the relationship between dynamic changes in cytokine expression levels and SAP disease progression and the relationship between cytokines, using continuous large-scale cytokine detection. Materials and Methods: Seventy rats were randomly assigned to control (Con), sham operation (SO) and SAP groups. The SAP group was randomly allocated to five subgroups at 3, 6, 9, 12 and 15 h after the operation. In the SAP group, 5% sodium taurocholate was injected retrograde into the pancreatic bile duct. Animals in the SO group received a similar incision, a turning over of the pancreas. Control animals did not receive any treatment. We observed the survival, ascites fluid amount, pancreatic histopathological scores and serum amylase activity of SAP rats. We used the cytokine microarray to simultaneously detect 90 cytokines and the dynamic changes in one experiment and to analyze the correlation between cytokine expression and disease progression. Results: The mortality of SAP rats increased with an increase in time. Serum amylase activity, pancreatic histopathological scores and ascites fluid amount were time-dependent. Compared with normal rats, 69 cytokines in SAP rats were significantly changed for at least one timepoint, and 49 cytokines were significantly changed at different timepoints after SAP induction. The changes in inflammatory cytokines were significantly upregulated at 6 and 9 h and 12 h and then significantly decreased. Conclusions: The trend of cytokine expression in SAP rats was not consistent with the disease progression. The cytokine-cytokine receptor interaction and MAPK signal's dominant cytokines were always highly expressed at various time points over the course of SAP.
Assuntos
Pancreatite , Animais , Doença Aguda , Ascite , Citocinas , Amilases , Progressão da DoençaRESUMO
Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.
Assuntos
Transtorno Depressivo Resistente a Tratamento/genética , Exossomos/genética , MicroRNAs/genética , Adolescente , Adulto , Idoso , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA/métodos , Adulto JovemRESUMO
OBJECTIVE: To detect the chemical constituents in Jianqu samples under different fermentated states by using UPLC-QTOF-MS/MS technology, to conduct preliminary analyses, and to establish an HPLC method for the simultaneous determination of hesperidin and naringenin in Jianqu, and the variation of the two components during fermentation were compared. METHODS: Waters ACQUITYTM UPLC HSST3 column (2.1 mm × 100 mm, 1.8 µm) was used; the mobile phase was 0.1% formic acid aqueous solution (A)-0.1% formic acid acetonitrile (B); The flow rate was 0.4 mL·min-1 with gradient elution; the column temperature was 45 °C; injection volume was 5 µL. The mass spectra of the samples were collected by negative ion mode under the electrospray ion source, and the data were screened and matched by UNIFI software. Hypersil gold C18 column (100 mm × 2.1 mm, 1.9 µm) was used; the mobile phase was acetonitrile (A)-0.1% acetic acid (B);; the flow rate with gradient elution was 0.3 mL·min-1; the column temperature was 30 °C; the injection volume was 2 µL. The content changes of hesperetin and naringenin in Jianqu at different fermentation time were detected. RESULTS: A total of 54 compounds were identified, including flavonoids, amino acids, organic acids, terpenoids, coumarins, lignans, and other compounds. Under the selected HPLC conditions, the linear relationship between hesperidin and naringenin was discovered (r2 = 0.9996). The content of hesperidin and naringenin changed significantly in the whole fermentation process. The highest concentration of content was observed at 36 h of fermentation and then decreased to varying degrees. CONCLUSION: This experiment can effectively identify various chemical components in Jianqu during different fermentation periods, and determine the content of the characteristic components, so as to provide a scientific basis for further study of Jianqu fermentation processing technology as well as a sound pharmacodynamic material basis.
Assuntos
Medicamentos de Ervas Chinesas , Hesperidina , Cromatografia Líquida , Espectrometria de Massas em Tandem , Hesperidina/análise , Medicina Tradicional Chinesa , Fermentação , Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta PressãoRESUMO
Sucrose preference test (SPT) is a most frequently applied method for measuring anhedonia, a core symptom of depression, in rodents. However, the method of SPT still remains problematic mainly due to the primitive, irregular, and inaccurate various types of home-made equipment in laboratories, causing imprecise, inconsistent, and variable results. To overcome this issue, we devised a novel method for automatic detection of anhedonia in mice using an electronic apparatus with its program for automated detecting the behavior of drinking of mice instead of manual weighing the water bottles. In this system, the liquid surface of the bottles was monitored electronically by infrared monitoring elements which were assembled beside the plane of the water surface and the information of times and duration of each drinking was collected to the principal machine. A corresponding computer program was written and installed in a computer connected to the principal machine for outputting and analyzing the data. This new method, based on the automated system, was sensitive, reliable, and adaptable for evaluation of stress- or drug-induced anhedonia, as well as taste preference and effects of addictive drugs. Extensive application of this automated apparatus for SPT would greatly improve and standardize the behavioral assessment method of anhedonia, being instrumental in novel antidepressant screening and depression researching.
Assuntos
Anedonia , Depressão/psicologia , Anedonia/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , SacaroseRESUMO
Glioma stem cells (GSCs) have been implicated in the promotion of malignant progression. Epidermal growth factor receptor variant (EGFRv) has been associated with glioma "stemness". However, the molecular mechanism is not clear. In this study, we were committed to investigate the role of EGFRv in GSCs and presented a new therapeutic target in EGFRvIII positive GSCs. The results showed that EGFRvIII could induce the expression of p-Src and PLK1, and both could induce the Notch1-SOX2 signaling pathway to promote self-renewal and tumor progression of GSCs. Mechanistically, both p-Src and PLK1 can induce Notch1, and the intracellular domain of Notch1 (NICD) can directly bind to SOX2, thereby promoting the maintenance of glioma stem cells. Furthermore, Saracatinib (Src inhibition) and BI2536 (PLK1 inhibition) diminished GSC self-renewal in vitro, and combining the two inhibitors increased survival of orthotopic tumor-bearing mice. Taken together, these data indicate that p-Src and PLK1 contribute to cancer stemness in EGFRvIII-positive GSCs by driving Notch1-SOX2 signaling, a finding that has important clinical implications.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Glioma/tratamento farmacológico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptor Notch1/genética , Fatores de Transcrição SOXB1/genética , Quinases da Família src/genética , Animais , Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/mortalidade , Humanos , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/farmacologia , Quinazolinas/farmacologia , Receptor Notch1/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Técnicas Estereotáxicas , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo , Quinase 1 Polo-LikeRESUMO
Survivin is a tumor-associated gene, which has been detected in a wide variety of human tumors. Previous research has shown that Survivin can affect hepatoma carcinoma cell radiosensitivity. However, little is known about the role of Survivin in ionizing radiation resistance in glioma cells. In this study, we aimed to identify the effects of Survivin on ionizing radiation resistance in glioma cell line T98. Our results showed that downregulation of Survivin gene expression and ionizing irradiation could both inhibit T98 cell proliferation by assays in vitro including CCK-8 and immunohistochemistry. The inhibitory effect of downregulation of Survivin combined with irradiation was the most significant compared with other groups. Results of Western blotting and flow cytometric analysis also showed that downregulation of Survivin combined with the irradiation group achieved the highest apoptosis rate. Experimental results in vivo by intracranial implanting into nude mice were consistent with those in vitro. These findings indicated that ionizing radiation resistance of human T98 glioma cells can be inhibited effectively after Survivin gene silencing.
Assuntos
Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/genética , Glioma/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Radiação Ionizante , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glioma/patologia , Humanos , Camundongos Nus , RNA Interferente Pequeno/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Glioma is the most common primary malignant tumor of the central nervous system, which results in both a poor prognosis and outcome because of the aggressive progression of disease, growth and resistance to surgery, chemotherapy, and radiotherapy. MiR-140-5p is a small, non-coding single-stranded RNA molecule, which was previously studied in the settings of human tongue cancer, hepatocellular carcinoma, and colorectal cancer. However, detailed data that formally demonstrate the contribution of miR-140-5p to glioma development are missing. Similarly, relatively little is known about the relationship of miR-140-5p, vascular endothelial growth factor A, and matrix metalloproteinase-2 in glioma progression. In this study, we found that miR-140-5p expression was significantly decreased in glioma tissues and in the glioma cell-lines U87 and U251 as compared with non-cancerous brain tissues by quantitative real-time polymerase chain reaction. In addition, miR-140-5p inhibited glioma cell proliferation and invasion and promoted glioma cell apoptosis both in vivo and in vitro. Interestingly, while the expression levels of miR-140-5p were higher in glioma cells, the messenger RNA or protein expression levels of vascular endothelial growth factor A and matrix metalloproteinase-2 were lower in glioma cells as determined by quantitative real-time polymerase chain reaction, western blot assay, and immunohistochemistry. By contrast, downregulation in the expression levels of miR-140-5p augmented the messenger RNA and protein expression levels of both vascular endothelial growth factor A and matrix metalloproteinase-2. These findings suggested that miR-140-5p inhibited glioma proliferation and invasion by regulating the vascular endothelial growth factor A/matrix metalloproteinase-2 signaling pathway both in vitro and in vivo.
Assuntos
Glioma/genética , Metaloproteinase 2 da Matriz/genética , MicroRNAs/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Animais , Apoptose/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Spalt-like transcription factor 4 (SALL4), a oncogene, is known to participate in multiple carcinomas, and is up-regulated in glioma. However, its actual role and underlying mechanisms in the development of glioma remain unclear. The present study explored the molecular functions of SALL4 in promoting cell proliferation in glioma. The expression level of SALL4 in 69 human glioma samples and six non-tumor brain tissues was determined using real-time polymerase chain reaction (PCR). Then, we transfected U87 and U251 cell lines with siRNA, and assessed cellular proliferation and cell cycle to understand the function of SALL4, and the relationship between SALL4, PTEN and PI3K/AKT pathway. PCR confirmed that the expression of SALL4 was higher in the glioma samples than non-tumor brain tissues. Cellular growth and proliferation were dramatically reduced following inhibition of SALL4 expression. Western blot showed increase in PTEN expression when SALL4 was silenced, which in turn depressed the activation of PI3K/AKT pathway, suggesting that PTEN was a downstream target of SALL4 in glioma development. Therefore, SALL4 could act as a proto-oncogene by regulating the PTEN/PI3K/AKT signaling pathway, thereby facilitating proliferation of glioma cells.
Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Neoplasias Encefálicas/patologia , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proto-Oncogene Mas , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genéticaRESUMO
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs.
Assuntos
Neoplasias Encefálicas/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo , Glioma/patologia , HumanosRESUMO
OBJECTIVE: The new glioma cell line SHG-139 was established and its phenotype, tumorigenicity, pathological characteristics, derived stem cells SHG139S were studied. METHODS: Immunohistochemistry was used to assess expressions in the patient and mouse tumor tissues, SHG-139 and SHG-139S. Primary SHG-139 culture was performed, cell proliferation, cell cycle and genetic characteristics were assessed. MiRNA (Micro RNA) and LncRNA (Long non-coding RNA) microarray was performed. RESULTS: We found that the glioma tissue was positive for A2B5 (Glial precursors ganglioside), GFAP (Glial fibrillary acidic protein), S-100 (Acid calcium bingding protein), VEGF (Vascular endothelial growth factor), VEGFR (Vascular endothelial growth factor receptor) and negative for Ki-67 (Nuclcar- associated antigen). SHG-139 proliferated significantly within 24h; its total number of chromosomes was 68; ratios of SHG-139 and SHG-139S cells in G1 phase were highest. SHG-139 cells were positive for A2B5, GalC (Galactocerebrosides), GFAP, S-100 and Vimentin, while SHG-139S cells were positive for A2B5, Nestin, and NG2 (Neuron-glia antigen2), and negative for Vimentin and IDHR132H (Isocitrate dehydrogenase); cells rarely stained for CD133 (Cluster of differentiation133). SHG-139 intracranial xenografts expressed GFAP, but no overt oligodendroglioma was observed. In SHG-139S xenografts, GFAP and S-100 were expressed, while CD133 was not detected; a few A2B5(+) cells were found at tumor edges, and typical oligodendroglioma were obtained. In addition, SHG-139S xenograft tumors were more aggressive than those of SHG-139. Anti-mouse CD31 (Cluster of differentiation31) staining revealed murine vessels at the border between xenograft tumor and normal brain tissue; Anti-human CD34 (Cluster of differentiation34) staining was negative. Biochip technology of SHG139S showed several miRNA and lncRNA were differently expressed in SHG139 and SHG139S. CONCLUSIONS: SHG-139 was an astroglioma cell line which yielded stem cells SHG-139S. SHG-139S cells constituted an A2B5(+)/CD133(-) GSC subgroup.
Assuntos
Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Glioma/diagnóstico , Glioma/genética , Xenoenxertos , Humanos , Imuno-Histoquímica , Cariótipo , Imageamento por Ressonância Magnética , Masculino , Camundongos , MicroRNAs/genética , Gradação de Tumores , Fenótipo , Células Tumorais Cultivadas , Adulto JovemRESUMO
Glioma has been investigated for decades, but the prognosis remains poor because of rapid proliferation, its aggressive potential, and its resistance to chemotherapy or radiotherapy. The mammalian target of rapamycin (mTOR) is highly expressed and regulates cellular proliferation and cell growth. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene transcription and translation via up-regulating or down-regulating the levels of miRNAs. This study was conducted to explore the molecular functions of miR-199a-3p in glioma. We detected the expression of miR-199a-3p in glioma samples by quantitative PCR (qPCR). Then, we transfected the U87 and U251 cell lines with miR-199a-3p. Cellular proliferation, invasion, and apoptosis were assessed to explain the function of miR-199a-3p. PCR confirmed that the expression of miR-199a-3p was lower in glioma samples combined with normal brain tissues. The over-expression of miR-199a-3p might target mTOR and restrained cellular growth and proliferation but not invasive and apoptosis capability. Results indicated that cellular proliferation was inhibited to regulate the AKT/mTOR signaling pathway by elevating levels of miR-199a-3p. MiR-199a-3p in glioma cell lines has effects similar to the tumor suppressor gene on cellular proliferation via the AKT/mTOR signaling pathway.
Assuntos
Proliferação de Células/genética , Glioma/genética , MicroRNAs/biossíntese , Serina-Treonina Quinases TOR/biossíntese , Apoptose , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Masculino , MicroRNAs/genética , Prognóstico , Serina-Treonina Quinases TOR/genéticaRESUMO
Malignant gliomas are the most common primary brain tumors, and the molecular mechanisms involving their progression and recurrence are still largely unclear. Substantial data indicate that the oncogene miR-494-3p is significantly elevated in gliomas, but the molecular functions of miR-494-3p in gliomagenesis are largely unknown. The present study aimed to explore the role of miR-494-3p and its molecular mechanism in human brain gliomas, malignant glioma cell lines, and cancer stem-like cells. The expression level of miR-494-3p in 48 human glioma issues and 8 normal brain tissues was determined using stem-loop real-time polymerase chain reaction (PCR). To study the function of miR-494-3p inhibitor in glioma cells, the miR-494-3p inhibitor lentivirus was used to transfect glioma cells. Transwell invasion system was used to estimate the effects of miR-494-3p inhibitor on the invasiveness of glioma cells. A mouse model was used to test the effect of miR-494-3p inhibitor on glioma proliferation and invasion in vivo. Results showed that the expression of miR-494-3p in human brain glioma tissues was higher than in normal brain tissues. Downregulated expression of miR-494-3p can inhibit the invasion and proliferation and promote apoptosis in glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that the expression of PTEN was increased after downexpression of miR-494-3p in glioma cells (U87 and U251). miR-494-3p inhibitor could prevent migration, invasion, proliferation, and promote apotosis in gliomas through PTEN/AKT pathway. Therefore, the study results have shown that miR-494-3p may act as a therapeutic target in gliomas.
Assuntos
Apoptose , Movimento Celular , Glioblastoma/genética , Glioblastoma/patologia , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/enzimologia , Humanos , Lentivirus/metabolismo , Masculino , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To establish a new glioma cell line and analyze its biological characteristics, and to provide a useful cellular tool with new features for cancer research. METHODS: Glioma tissue was taken from surgical specimen clinical of a clinical patient. Primary culture was carried out, and a cell line (SHG139) was established after 10 passages. Immunofluorescence staining was performed to detect the expression of proteins, and cell proliferation and cycle were detected by flow cytometry method (FCM). The biological characteristics of SHG139 cells were detected by chromosome karyotype analysis. SHG139s glioma cells derived from SHG139 glioma cell line were cultured with neural stem cell medium. Then stem cell markers were determined. SHG139s cells were induced with serum-containing medium, and their expression of A2B5, GFAP, ß-III tubulin, and GalC was detected. Intracranial xenograft tumor of both SHG139 glioma cells and SHG139s glioma stem cell spheres was generated in rats. RESULTS: The expressions of A2B5, GalC, GFAP, S-100, and vimentin in the 20 and 60 passages of SHG139 cells were positive, consistent with the immunohistochemical results and pathological features. SHG139 cells proliferated significantly within 24 h after subculture, and their total number of chromosomes was 68 and mostly multiploid. They were positive for A2B5 (84.12±9.96)%, nestin (73.86±5.01)%, and NG2 (73.37±2.09)%. SHG139s cells were induced, and the ratio of positive cells of GFAP, ß-III tubulin and GalC was (92.89±2.24)%, (64.85±4.09)% and (33.57±4.14)%, respectively. CONCLUSIONS: SHG139 is an astroglioma cell line, from which SHG139s cells can be successfully obtained by culture with NSCM. SHG139s cells are of A2B5(+)/CD133(-) GSCs subgroup cells, with potentials of self-renewal and multi-directional differentiation. Compared with the intracranial SHG139 xenograft tumor, the intracranial SHG139s xenograft tumor is more malignant and aggressive.
Assuntos
Glioma , Animais , Astrocitoma , Neoplasias Encefálicas , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Citometria de Fluxo , Humanos , Células-Tronco Neoplásicas , Nestina , Ratos , Transplante Heterólogo , VimentinaRESUMO
Recent studies have identified a class of small non-coding RNA molecules, named microRNA (miRNA), that is dysregulated in malignant brain glioblastoma. Substantial data have indicated that miRNA-16 (miR-16) plays a significant role in tumors of various origins. This miRNA has been linked to various aspects of carcinogenesis, including cell apoptosis and migration. However, the molecular functions of miR-16 in gliomagenesis are largely unknown. We have shown that the expression of miR-16 in human brain glioma tissues was lower than in non-cancerous brain tissues, and that the expression of miR-16 decreased with increasing degrees of malignancy. Our data suggest that the expression of miR-16 and nuclear factor (NF)-κB1 was negatively correlated with glioma levels. MicroRNA-16 decreased glioma malignancy by downregulating NF-κB1 and MMP9, and led to suppressed invasiveness of human glioma cell lines SHG44, U87, and U373. Our results also indicated that upregulation of miR-16 promoted apoptosis by suppressing BCL2 expression. Finally, the upregulation of miR-16 in a nude mice model of human glioma resulted in significant suppression of glioma growth and invasiveness. Taken together, our experiments have validated the important role of miR-16 as a tumor suppressor gene in glioma growth and invasiveness, and revealed a novel mechanism of miR-16-mediated regulation in glioma growth and invasiveness through inhibition of BCL2 and the NF-κB1/MMP-9 signaling pathway. Therefore, our experiments suggest the possible future use of miR-16 as a therapeutic target in gliomas.
Assuntos
Neoplasias Encefálicas/metabolismo , Proliferação de Células , Glioma/metabolismo , MicroRNAs/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais , Animais , Apoptose , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Subunidade p50 de NF-kappa B/metabolismo , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Carga TumoralRESUMO
Breast cancer, as one of the most common malignancies in women, exhibits complex and heterogeneous pathological characteristics across different subtypes. Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are two common and highly invasive subtypes within breast cancer. The stability of the breast microbiota is closely intertwined with the immune environment, and immunotherapy is a common approach for treating breast cancer.Tertiary lymphoid structures (TLSs), recently discovered immune cell aggregates surrounding breast cancer, resemble secondary lymphoid organs (SLOs) and are associated with the prognosis and survival of some breast cancer patients, offering new avenues for immunotherapy. Machine learning, as a form of artificial intelligence, has increasingly been used for detecting biomarkers and constructing tumor prognosis models. This article systematically reviews the latest research progress on TLSs in breast cancer and the application of machine learning in the detection of TLSs and the study of breast cancer prognosis. The insights provided contribute valuable perspectives for further exploring the biological differences among different subtypes of breast cancer and formulating personalized treatment strategies.