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Lung cancer is one of the most common malignant tumors and has a poor prognosis and a low survival rate. Traditional treatments, such as radiotherapy and chemotherapy, still face some challenges because of high drug resistance and toxicity. Therefore, it is necessary to discover a new kind of targeted drug with low toxicity and high efficiency. CDK12 is a cell cycle-dependent kinase whose main function is to activate RNA polymerase II (RNAPII) and promote the transcriptional extension of RNA. However, the role and molecular mechanism of CDK12 in lung cancer are still unclear. In this study, the mutation and RNA-Seq data of CDK12 in lung adenocarcinoma and squamous cell carcinoma were downloaded from The Cancer Genome Atlas (TCGA) database and analyzed with the custom scripts. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and cell colony formation assays. A subcutaneous tumor experiment in nude mice was used to examine the effects of CDK12 knockdown on the in vivo tumor growth of NSCLC cells. The cell cycle distribution and the apoptosis rate of lung cancer cells were assessed by flow cytometry. Regulation of TANK-binding kinase 1 (TBK1) by CDK12 was evaluated by quantitative PCR, immunoprecipitation and Western blot analysis. In this study we have analyzed the mutation and expression data of The Cancer Genome Atlas (TCGA) database and found that CDK12 is highly expressed in lung cancer tissues. Clinical correlation analysis showed that high expression of CDK12 in NSCLC reduces patient survival, but its high expression is only related to early tumor progression and has no significant correlation with late tumor progression and metastasis. Furthermore, we present evidence that CDK12 depletion in lung cancer cell lines not only leads to the inhibition of cell growth and induces apoptosis but also inhibits tumor growth of NSCLC cells in vivo. CDK12 positively regulates the expression of the oncogene TBK1 in lung cancer cells. These results revealed that CDK12 affects the progression of non-small cell lung cancer through positive regulation of TBK1 expression, suggesting that CDK12 might be a potential molecular target for the treatment of non-small cell lung cancer.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Adenocarcinoma de Pulmão/genética , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , Camundongos Nus , HumanosRESUMO
It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Dineínas do Citoplasma/genética , Imunidade/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Transdução de Sinais/genética , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Interferon gama/genética , Janus Quinase 1/genética , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição STAT/genética , Microambiente Tumoral , Regulação para Cima/genéticaRESUMO
High-energy density and low-cost sodium-ion batteries are being sought to meet increasing energy demand. Here, R-MnO2 is chosen as a cathode material of sodium-ion batteries owing to its low cost and high energy density. The structural transformation from the tunnel R-MnO2 to the layered NaMnO2 and electrochemical properties during the charge/discharge are investigated at the atomic level by combining XRD and related electrochemical experiments. Na≤0.04MnO2 has a tunnel R-MnO2 phase structure, Na≥0.42MnO2 has a layered NaMnO2 phase structure, and Na0.04-0.42MnO2 is their mixed phase. Mn3+ 3d4[t2gß3dz2(1)3dx2-y2(0)] in NaMnO2 loses one 3dz2 electron and the redox couple Mn3+/Mn4+ delivers 206 mA h g-1 during the initial charge. The case that the Fermi energy level difference between R-MnO2 and NaMnO2 is lower than that between the layered Na(12-x)/12MnO2 and NaMnO2 makes the potential plateau of R-MnO2 turning into NaMnO2 lower than that of the layered Na(12-x)/12MnO2 to NaMnO2. This can be confirmed by our experiment from the 1st-2nd voltage capacity profile of R-MnO2 in EC/PC (ethylene carbonate/propylene carbonate) electrolyte. The study would give a new view of the production of sustainable sodium battery cathode materials.
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OBJECTIVE: There are few studies regarding Internet use behaviors of Chinese rural adolescents based on behavioral theory. The aim of this study is to examine the applicability and effectiveness of the health action process approach model (HAPA) in the intervention of excessive Internet use behaviors among rural adolescents in China. METHODS: Three hundred twenty-seven participants who met the excessive Internet use criteria were involved in this study. Four interventions based on the HAPA model were conducted during 2015-2017. The structural equation model (SEM) was applied to fit the HAPA model. RESULTS: The rate of average daily time spent online on weekends more than 4 h dropped from 57.2 to 39.1% (P < 0.001). The rate of daily game time more than 2 h decreased from 51.1 to 35.2% (P < 0.001). The result of SEM showed that both the applicability and effectiveness of the HAPA model were well in the intervention of excessive Internet use behaviors with good fitted indicators (χ2/df = 2.066, GFI = 0.889, CFI = 0.938, TLI = 0.928, IFI = 0.938, RMSEA = 0.057). The direct and indirect effects of the main pathways in the HAPA model were statistically significant (P < 0.05). The comparison analysis of HAPA model variables identified that outcome expectancy, intention, maintenance self-efficacy had been improved significantly after interventions. CONCLUSION: The intervention measures based on the HAPA model can effectively reduce excessive Internet use behaviors of Chinese rural adolescents, mainly through strengthen outcome expectancy, intention, and maintenance self-efficacy.
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Intenção , Uso da Internet , Adolescente , China/epidemiologia , Humanos , Internet , Projetos Piloto , Instituições AcadêmicasRESUMO
E3 ubiquitin ligases, which are key enzymes in the ubiquitin proteasome system, catalyze the ubiquitination of proteins to target them for proteasomal degradation. Emerging evidence suggests that E3 ubiquitin ligases play important roles in the development and progression of lung cancer. In our study, we characterized the gene expression landscape of lung cancer using data obtained from TCGA to explore the changes in E3 ubiquitin ligase containing the regulators of E3 ubiquitin ligase activity. Overall, most gene expression changes occurred in NSCLC tissues compared with adjacent normal ones. In total, 48 E3 ubiquitin ligases containing the regulators were up-regulated in NSCLC tissues compared with their levels in normal tissues. We analyzed the expression of up-regulated E3 ubiquitin ligases containing the regulators in two publicly available transcriptome data sets (GSE13213 and GSE30219). We found that four E3 ubiquitin ligases (UHRF1, BRCA1, TRAIP and HLTF) and one regulator of ubiquitin E3 activity DCUN1D1 that were dramatically up-regulated in cancer were significantly associated with tumor metastasis and patient's poor prognosis both in two transcriptome data sets. Next, clinical analysis indicated that the expression levels of DCUN1D1 correlated with clinical stage and lymph node metastasis in NSCLC patients as determined by quantitative reverse transcription-PCR. Furthermore, functional assays showed that DCUN1D1 promoted NSCLC cell invasion and migration as determined by transwell assay in vitro. Mechanistically, we found that the C-terminal Cullin binding domain leads to oncogenic activity and the UBA domain acts as a negative regulator of DCUN1D1 function in NSCLC. Moreover, DCUN1D1 activated the FAK oncogenic signaling pathway and up-regulated PD-L1. Taken together, our results demonstrate that DCUN1D1 is a metastasis regulator and suggest a new therapeutic option for NSCLC metastasis.
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Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Quinase 1 de Adesão Focal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Transdução de Sinais/genética , Células A549 , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/patologia , Metástase Neoplásica/patologia , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica/genética , Ativação Transcricional/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: microRNAs can repress the expression of target genes by destabilizing their mRNAs or by inhibiting their translation. Our previous findings suggested that miR-193a-3p inhibited the progression of NSCLC both in vitro and in vivo. However, the biological processes and molecular pathways through which this miRNA exerts its positive effects are unknown. METHODS: To explore the molecular mechanisms by which miR-193a-3p inhibited NSCLC metastasis, we investigated the changes in the protein profile of SPC-A-1sci (highly metastatic) cells in response to the up-regulation of miR-193a-3p expression using a proteomics approach (iTRAQ combined with NanoLC-MS/MS). Changes in the profiles of the expressed proteins were verified using western blotting and were analyzed using the DAVID and STRING programs. RESULTS: In the two replicated experiments, 4962/4946 proteins were identified, and the levels of expression of 4923/4902 proteins were quantified. In total, 112 of these proteins were differentially expressed. Among them, the up-regulated levels of expression of two of the 62 proteins with up-regulated expression (PPP2R2A and GSN) and the down-regulated levels of expression four of the 50 proteins with down-regulated expression (LMNB2, UHRF1, G3BP1, and HNRNPU) were verified using western blotting. The bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins. CONCLUSION: miR-193a-3p inhibited the metastasis of lung cancer cells by deregulating the expression of tumor-related proteins. These findings may improve the understanding of the molecular mechanisms underlying the metastatic-inhibitory effect of miR-193a-3p on lung cancer cells.
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MicroRNAs/metabolismo , Proteômica , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Bases de Dados Factuais , Regulação para Baixo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Oligonucleotídeos Antissenso/metabolismo , Mapas de Interação de Proteínas , Espectrometria de Massas em Tandem , Regulação para CimaRESUMO
BACKGROUND/AIMS: microRNAs (miRNAs) are noncoding RNAs that regulate multiple targets through either the degradation of mRNAs or the inhibition of protein translation, thereby altering several functions simultaneously. Growing evidence indicates that miRNAs are involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). METHODS: In this study, the mRNA expression levels of miR-148a were examined in NSCLC cell lines and patient specimens using quantitative reverse transcription-PCR. The functions of miR-148a in migration/invasion and lung metastasis formation were determined by using transwell and tail vein injection assays, respectively. RESULTS: We demonstrated that miR-148a was down-regulated in NSCLC metastatic samples, and its expression was suppressed in NSCLC compared with the corresponding nonmalignant lung tissues. Clinical analysis indicated that miR-148a expression was lower in NSCLC patients compared with nonmalignant lung tissues . Decreased miR-148a was significantly associated with tumor node metastasis stage and lymph node metastasis. Furthermore, functional assays showed that miR-148a expression suppressed NSCLC cell invasive and migratory abilities in vitro and suppressed cancer metastasis in vivo, while inhibition of miR-148a enhanced NSCLC cell invasion and lung metastasis formation in a mouse model. CONCLUSIONS: Evidence from this study demonstrated that miR-148a exerts tumor-suppressive effects in NSCLC and suggests a new therapeutic option for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Feminino , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Growing evidence indicates that miR-200c is involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). However, its precise biological role remains largely elusive. METHODS: The functions of miR-200c and USP25 in migration/invasion and lung metastasis formation were determined by transwell and tail vein injection assays, respectively. The potential regulatory targets of miR-200c were determined by prediction tools, correlation with target protein expression, and luciferase reporter assay. The mRNA expression levels of miR-200c and USP25 were examined in NSCLC cell lines and patient specimens using quantitative reverse transcription-PCR. The protein expression levels of USP25 were examined in NSCLC cell lines and patient specimens using western blot and immunohistochemical staining. RESULTS: We demonstrated that over-expression of miR-200c inhibited NSCLC cells migration, invasion, epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. Further studies revealed that USP25 was a downstream target of miR-200c in NSCLC cells as miR-200c bound directly to the 3'-untranslated region of USP25, thus reducing both the messenger RNA and protein levels of USP25. Silencing of the USP25 gene recapitulated the effects of miR-200c over-expression. Clinical analysis indicated that miR-200c was negatively correlated with clinical stage, lymph node metastasis in NSCLC patients. Moreover, USP25 protein and mRNA level expressions were higher in NSCLC patients, compared to healthy control, and correlated with clinical stage and lymphatic node metastasis. CONCLUSIONS: These findings indicate that miR-200c exerts tumor-suppressive effects for NSCLC through the suppression of USP25 expression and suggests a new therapeutic application of miR-200c in the treatment of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Ubiquitina Tiolesterase/genética , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologiaRESUMO
Background: Lung cancer is the most common primary malignant tumor of the lung, and as one of the malignant tumors that pose the greatest threat to the health of the population, the incidence rate has remained high in recent years. Previous studies have shown that KLRB1 is transcriptionally repressed in lung adenocarcinoma and correlates with lung adenocarcinoma prognosis. The objective of this study is to investigate the intrinsic mechanisms by which KLRB1 affects the malignant phenotypes of lung adenocarcinoma such as immune infiltration, proliferation, growth and metastasis. Methods: We assessed the expression levels of KLRB1 in publicly available databases and investigated its associations with clinical and pathological variables. Enrichment analysis was subsequently conducted to investigate possible signaling pathways and their associated biological functions. Statistical analysis, including Spearman correlation and the application of multigene prediction models, was utilized to assess the relationship between the expression of KLRB1 and the infiltration of immune cells. The diagnostic and prognostic value of KLRB1 was evaluated using Kaplan-Meier survival curves, diagnostic receptor operating characteristic (ROC) curves, histogram models, and Cox regression analysis. Specimens from lung adenocarcinoma (LUAD) patients were collected, the expression level of KLRB1 was detected by protein blotting analysis, and the expression level of KLRB1 was detected at the mRNA level by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Small interfering RNA (siRNA) was used to silence gene expression, and Transwell, Cell Counting Kit-8 (CCK-8) and colony formation assays were subsequently performed to analyze the effects of KLRB1 on LUAD cell migration, invasion and proliferation. Results: KLRB1 expression was lower in lung cancer tissue than in surrounding healthy tissue. Genes differentially expressed in the low and high KLRB1 expression groups were found to be significantly enriched in pathways related to immunity. KLRB1 exerted an impact on the MAPK/ERK signaling pathway, thereby modulating the growth and proliferation of LUAD cells. KLRB1 expression is linked to prognosis, immune infiltration, and cell migration and proliferation in LUAD. Conclusions: The evidence revealed a correlation between KLRB1 and both prognosis and immune infiltration in LUAD patients.
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Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive malignant soft tissue tumor with a poor prognosis; however, the identity and heterogeneity of tumor populations remain elusive. Here, eight major cell clusters were identified through the RNA sequencing of 79,569 individual cells of UPS. UPS originates from mesenchymal stem cells (MSCs) and features undifferentiated subclusters. UPS subclusters were predicted to exist in two bulk RNA datasets, and had a prognostic value in The Cancer Genome Atlas (TCGA) dataset. The functional heterogeneity of malignant UPS cells and the immune microenvironment were characterized. Additionally, the fused cells were innovatively detected by expressing both monocyte/macrophage markers and other subcluster-associated genes. Based on the ligand-receptor interaction analysis, cellular interactions with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) were abundant. Furthermore, 73% of patients with UPS (48/66) showed positive EGFR expression, which was associated with a poor prognosis. EGFR blockade with cetuximab inhibited tumor growth in a patient-derived xenograft model. Our transcriptomic studies delineate the landscape of UPS intratumor heterogeneity and serve as a foundational resource for further discovery and therapeutic exploration.
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Receptores ErbB , Sarcoma , Análise de Célula Única , Humanos , Animais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Camundongos , Sarcoma/patologia , Sarcoma/genética , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão GênicaRESUMO
To discover metastasis-associated proteins within cancer cells, we used the isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with nano liquid chromatography-tandem mass spectrometry (NanoLC-MS/MS) analysis to identify proteins that were differentially expressed between lung adenocarcinoma cancer cell lines SPC-A-1sci cells with high metastatic potential and parent SPC-A-1 cells with low metastatic potential. By employing biological and technical replicates, we identified 5818 nonredundant proteins and quantified 5443 proteins, 256 of which were differentially expressed in the two cell lines. Through si-RNA-mediated functional screens, Myosin heavy chain 9 (MYH9) and Copine III (CPNE3) were indicated as positively correlating with the migration and invasion properties of SPC-A1sci cells, and the same function of CPNE3 was confirmed in another lung cancer cell line, H1299. Furthermore, overexpressing CPNE3 promoted nonsmall-cell lung cancer (NSCLC) cell line (SPC-A-1 and XL-2) migration and invasion in vitro. Moreover, the targeted knock-down of CPNE3 inhibited the in vivo metastatic abilities of H1299 cells in mouse models. Lastly, immunohistochemistry revealed that the CPNE3 expression level was positively correlated with the clinical stage and TNM classification in NSCLC patients. Taken together, our results indicate that CPNE3 could play a critical role in NSCLC metastasis.
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Carcinoma Pulmonar de Células não Pequenas/genética , Metástase Neoplásica/genética , Proteínas de Neoplasias/isolamento & purificação , Fosfoproteínas/biossíntese , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Cromatografia Líquida , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas Motores Moleculares/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Proteoma/análise , Espectrometria de Massas em TandemRESUMO
Hepatocellular carcinoma (HCC) is one of the most deadly human cancers, but it is very difficult to establish an animal model by using surgical specimens. In the present experiment, histologically intact fresh surgical specimens of HCC were subcutaneously transplanted in non-obese diabetic/severe combined immunodeficienccy (NOD/SCID) mice. The biological characteristics of the original and the corresponding transplanted tumors and cell lines were investigated. The results showed that 5 new animal models and 2 primary cell lines were successfully established from surgical specimens. Hematoxylin-eosin staining showed that xenografts retained major histological features of the original surgical specimens. The two new cell lines had been cultivated for 3 years and successively passaged for more than 100 passages in vitro. The morphological characteristics and biologic features of the two cell lines were genetically similar to the original tumor. The subcutaneous transplant animal models with histologically intact tumor tissue and primary cell lines could be useful for in vivo and in vitro testing of anti-cancer drugs and be ideal models to study various biologic features of HCC.
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Background Previous studies have been inconsistent about the association between age at menarche and high blood pressure. Little is known about such association across a wide range of menarcheal ages in less developed ethnic minority regions in China. We aimed to explore the association between age at menarche and high blood pressure (BP; ≥140/90 mm Hg) and to examine the mediating effect of obesity and the moderating effect of menopausal status on this association. Methods and Results A total of 45 868 women from the baseline data of the CMEC (China Multi-Ethnic Cohort) were included in this study. Binary logistic regression was used to analyze the relationship between age at menarche and high BP, and the mediation model was used to evaluate the mediating effects of body mass index and waist circumference on the association of age at menarche with high BP. The mean age at enrollment and age at menarche of participants in our study were 49.3 (SD=10.7) and 14.7 (SD=2.1) years, respectively. Late menarche was associated with a lower risk of high BP (odds ratio, 0.831 [95% CI, 0.728-0.950]). The risk of high BP decreased by 3.1% with each year's delay in the onset of menarche (P for trend <0.001). Body mass index and waist circumference could partially mediate the association of age at menarche and high BP with the indirect effect of body mass index (odds ratio, 0.998 [95% CI, 0.997-0.998]) and waist circumference (odds ratio, 0.999 [95% CI, 0.998-0.999]). In addition, the mediation effects were modified by the status of menopause. Conclusions Women with late menarche have a lower risk of high BP, and obesity could be one of the important mediators. Obesity prevention is an efficient strategy to reduce the association between age at menarche and high BP, especially in premenopausal women.
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Hipertensão , Menarca , Humanos , Feminino , Pressão Sanguínea/fisiologia , Etnicidade , Grupos Minoritários , Obesidade/epidemiologia , Hipertensão/epidemiologia , China/epidemiologia , Modelos LogísticosRESUMO
UNLABELLED: Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3ß and lead to ß-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide). CONCLUSION: For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.
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Acetilcolinesterase/metabolismo , Acetilcolinesterase/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Etoposídeo/farmacologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida , Transplante HeterólogoRESUMO
UNLABELLED: Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1α (HIF-1α) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin ß1 axis. CONCLUSION: ANGPTL4 is a target gene of HIF-1α and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients.
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Angiopoietinas/fisiologia , Carcinoma Hepatocelular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neoplasias Hepáticas/metabolismo , Transdução de Sinais , Adulto , Idoso , Proteína 4 Semelhante a Angiopoietina , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Células Endoteliais/metabolismo , Feminino , Humanos , Integrina beta1/fisiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Molécula 1 de Adesão de Célula Vascular/fisiologiaRESUMO
Soyasaponins are naturally occurring triterpenoid glycosides associated with many biological activities. The aim of the present study was to develop an effective method for isolation and purification of differently glycosylated, acetylated, and 2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP)-conjugated soyasaponins from soy hypocotyls. Both gel filtration using Sephadex LH-20 chromatography (Amersham Pharmacia Biotech AB; elution phase: methanol, flow rate: 3.0 mL/min, sample loading: 60 mg) and high-speed countercurrent chromatography (stationary phase: n-butanol-acetic acid (5.0%, v/v), mobile phase: water flow rate: 3.0 mL/min, sample loading: 100 mg) could effectively fractionate isoflavones and soyasaponins from the crude extract with yield of soyasaponin complexes 20.5 mg and 22.3 mg, respectively. After fractionation, the soyasaponin complexes could be purified further using preparative HPLC to separate individuals. A total of nine soyasaponins, triacetyl soyasaponin Ab (yield 1.55%, HPLC purity >98%), Aa (2.68%, >99%), Ab (18.53%, >98%), Ae (0.85%, >98%), Ba (0.63%, >91%), Af (1.12%, >85%), Bb (3.45%, >98%) and Be (0.59%, >76.8%) were obtained. DDMP-conjugated groups, αg (2.06%, >85%), ßg (7.59%, >85%), and γg (0.29%, >85%) that were very labile even in mild conditions, were also collected. The method described here can be used as an effective protocol to separate different soyasaponins occurring in the original sample.
Assuntos
Cromatografia em Gel/métodos , Cromatografia Líquida de Alta Pressão/métodos , Distribuição Contracorrente/métodos , Glycine max/química , Hipocótilo/química , Extratos Vegetais/isolamento & purificação , Saponinas/isolamento & purificação , Extratos Vegetais/análise , Saponinas/análiseRESUMO
UNLABELLED: MicroRNAs (miRNAs) are small, noncoding RNAs that can act as oncogenes or tumor suppressors in human cancer. Our previous study showed that miR-125b was a prognostic indicator for patients with hepatocellular carcinoma (HCC), but its functions and exact mechanisms in hepatic carcinogenesis are still unknown. Here we demonstrate that miR-125b suppressed HCC cell growth in vitro and in vivo. Moreover, miR-125b increased p21Cip1/Waf1 expression and arrested cell cycle at G1 to S transition. In addition, miR-125b inhibited HCC cell migration and invasion. Further studies revealed that LIN28B was a downstream target of miR-125b in HCC cells as miR-125b bound directly to the 3' untranslated region of LIN28B, thus reducing both the messenger RNA and protein levels of LIN28B. Silencing of LIN28B recapitulated the effects of miR-125b overexpression, whereas enforced expression of LIN28B reversed the suppressive effects of miR-125b. CONCLUSION: These findings indicate that miR-125b exerts tumor-suppressive effects in hepatic carcinogenesis through the suppression of oncogene LIN28B expression and suggest a therapeutic application of miR-125b in HCC.
Assuntos
Divisão Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Neoplasias Hepáticas/patologia , MicroRNAs/farmacologia , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Proteínas de Ligação a DNA/antagonistas & inibidores , Regulação para Baixo , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , Proteínas de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
UNLABELLED: The pathological relevance and significance of microRNAs (miRNAs) in hepatocarcinogenesis have attracted much attention in recent years; however, little is known about the underlying molecular mechanisms through which miRNAs are involved in the development and progression of hepatocellular carcinoma (HCC). In this study, we demonstrate that miR-30d is frequently up-regulated in HCC and that its expression is highly associated with the intrahepatic metastasis of HCC. Furthermore, the enhanced expression of miR-30d could promote HCC cell migration and invasion in vitro and intrahepatic and distal pulmonary metastasis in vivo, while silencing its expression resulted in a reduced migration and invasion. Galphai2 (GNAI2) was identified as the direct and functional target of miR-30d with integrated bioinformatics analysis and messenger RNA array assay. This regulation was further confirmed by luciferase reporter assays. In addition, our results, for the first time, showed that GNAI2 was frequently suppressed in HCC by way of quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining assays. The increase of the GNAI2 expression significantly inhibits, whereas knockdown of the GNAI2 expression remarkably enhances HCC cell migration and invasion, indicating that GNAI2 functions as a metastasis suppressor in HCC. The restoration of GNAI2 can inhibit miR-30d-induced HCC cell invasion and metastasis. CONCLUSION: The newly identified miR-30d/GNAI2 axis elucidates the molecular mechanism of HCC cell invasion and metastasis and represents a new potential therapeutic target for HCC treatment.
Assuntos
Carcinoma Hepatocelular/genética , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/fisiologia , Neoplasias Hepáticas/genética , MicroRNAs/fisiologia , Carcinoma Hepatocelular/secundário , Humanos , Neoplasias Hepáticas/patologia , Invasividade Neoplásica , Células Tumorais CultivadasRESUMO
Objective: To explore the change in the prevalence and association of depression and deliberate self-harm and their common and independent influencing factors among western Chinese rural adolescents. Methods: A total of 2,744 junior and senior high school students from two rural schools in Sichuan Province, China, participated in the baseline survey and were invited to participate in two follow-up surveys. The Center for Epidemiologic Studies-Depression Scale, a deliberate self-harm item, the Social Support Rating Scale, the Rosenberg Self-esteem Scale and the Connor-Davidson Resilience Scale were administered. A bivariate four-level logistic regression model was used for analysis. Results: The prevalence of depression and deliberate self-harm were 39.6 and 21.2%, respectively. Regular physical exercise, a good relationship with parents, high resilience, and high self-esteem were common protective factors for both depression and deliberate self-harm. Feeling disliked by teachers was a common risk factor for both. Being female, having a mother who emigrated as a migrant worker before the student was 3 years old, feeling disliked by classmates and having a poor family economic status were associated only with an increased risk of depression. Participants with medium social support were less likely to report deliberate self-harm than those with low or high support. Depression and deliberate self-harm were clustered at the class level. Conclusions: The comorbidity of depression and deliberate self-harm in rural adolescents should be given ample attention. Interventions should consider the class clustering of depression and deliberate self-harm and their common and unique influencing factors.
RESUMO
Due to the high theoretical specific capacity and low cost, FeF3·0.33H2O has become one of the potential choices of cathode materials for sodium-ion batteries. However, the poor intrinsic conductivity limits its practical applications. Herein, the atomic substitution is used to improve its intrinsic conductivity. The first-principles calculation results show that Cr3+ doping can reduce the band gap of FeF3·0.33H2O to improve its intrinsic conductivity. The discharge specific capacity of Fe0.95Cr0.05F3·0.33H2O with a narrowest band gap is 194.02 mA h/g at 0.1 C within the range of 1.4-4.0 V, which is higher than that of FeF3·0.33H2O (136.47 mA h/g). Using the electrochemical impedance spectroscopy and galvanostatic intermittent titration technique tests, it is found that Rct of Fe0.95Cr0.05F3·0.33H2O is reduced and DNa+ is almost unchanged, as compared to FeF3·0.33H2O.