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1.
Kaohsiung J Med Sci ; 36(5): 363-370, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31943723

RESUMO

Recurrent pregnancy loss (RPL) is three or more times of consecutive spontaneous loss of pregnancy. The underlying cause is complicated and the etiology of over 50% of RPL patients is unclear. In the present study, bone marrow mesenchymal stem cells were isolated from CBA/J female mice and exosomes were isolated from cell culture medium by ultracentrifugation. CBA/J female mice were paired with male DBA/2 to generate abortion prone mouse model, and CBA/J females paired with male BALB/c mice were used as control. Exosomes were injected through uterine horns into pregnant CBA/J mice on day 4.5 of gestation in abortion-prone matting. On day 13.5 of pregnancy, abortion rates were calculated and the level of transforming growth factor-ß (TGF-ß), interleukin 10 (IL-10), interferon g (IFN-γ), and tumor necrosis factor a (TNF-α) in CD4+ T cells and macrophages in deciduas were evaluated by flow cytometry. Exosomes injection improved the pregnancy outcomes in abortion prone mice. The IL-4 and IL-10 levels on CD4+ T cells were upregulated in the maternal-fetal interface; meanwhile, the TNF-α and IFN-γ levels on CD4+ T cells were reduced. The IL-10 level was increased and IL-12 was reduced on the monocytes that separated from deciduas. miR-101 level was increased in the CD4+ T cells in the deciduas. In conclusion, the treatment of ESCs-derived exosomes modulates T cells' function and macrophages activities in the maternal-fetal interface that resulted in a decreased embryo resorption rate, and provides a therapeutic potential to treat RPL.

2.
Horm Cancer ; 10(4-6): 177-189, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713780

RESUMO

In hepatocellular carcinoma (HCC), the hypoxic tumor microenvironment can drive enhance tumor malignancy and recurrence. The microRNA (miRNA) miR-196-5p has been shown to modulate the progression of several cancer types, but its roles in HCC remain uncertain. In the present report we observed significant miR-196-5p downregulation in HCC tissues and cells, and we found that the expression of this miRNA significantly impaired the proliferation and metastatic potential of HCC in vitro and in vivo. We identified high-mobility group AT-hook 2 (HMGA2) as a miR-196-5p target gene that was associated with the ability of miR-196-5p to modulate the progression of HCC. Expression of miR-196-5p and HMGA2 were correlated with the clinical characteristics and poor outcomes in patients with HCC. Finally, we found that hypoxic conditions were linked with reduced miR-196-5p expression in the context of HCC. Together these results highlight the role for miR-196-5p as an inhibitor of the proliferation and metastasis of HCC via the targeting of HMGA2, with this novel hypoxia/miR-196-5p/HMGA2 pathway serving as a potential target for future therapeutic intervention.

3.
Surg Oncol ; 31: 67-74, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541909

RESUMO

The molecular mechanisms governing the metastasis of colorectal cancer (CRC) are incompletely understood. In the present study, we found NOVA1 to be expressed at higher levels in CRC cell lines and tissue samples, and this upregulation was positively correlated with TNM stage (p = 0.034), poor differentiation (p = 0.001), and lymph node metastasis (p = 0.008). Both overall survival (OS) and relapse-free survival (RFS) were both significantly decreased in patients with high NOVA1 expression relative to those with low expression. Through a multivariate analysis, we determined that NOVA1 independently predicted poor outcomes in those with CRC. In further functional studies, we found that NOVA1 expression controlled the proliferation and invasive characteristics of CRC cells via a mechanism wherein NOVA1 bound and stabilized the IL6 mRNA, enhancing IL-6/JAK2/STAT3 signaling to in turn upregulate matrix metalloproteinases (MMPs) 2, 7, and 9. NOVA1 therefore plays key functional roles in regulating CRC progression, and our results further indicate that it serve as a valuable prognostic biomarker and potentially a target for therapeutic treatment in individuals with CRC.

4.
Onco Targets Ther ; 12: 5849-5860, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410028

RESUMO

Background: Circular RNAs (circRNAs) play important roles in the progression of cancers, but the precise role of circRNAs in the diagnosis and prognosis of hepatocellular carcinoma (HCC) remains to be clarified. The aim of the current study was to explore the diagnostic and prognostic values of hsa_circ_0003998 in HCC. Methods: CircRNAs expression was measured using RNA-seq analysis from HCC tissues (n=6) (three cases with or without portal vein invasion). Hsa_circ_0003998 in 200 pairs of HCC and adjacent noncancerous tissues and HCC cell lines was examined using qRT-PCR and the clinicopathologic significance was determined. We also detected the plasma levels of hsa_circ_0003998 in HCC, hepatitis B patients and healthy controls. The clinical diagnosis and prognostic values were further determined using receiver operating characteristic (ROC) curve, Kaplan-Meier curve and Cox regression. Results: Hsa_circ_0003998 was upregulated in HCC tissues (P<0.001) and HCC cell lines (HepG2, HuH7, MHCC97H) (P<0.001). In addition, upregulation of hsa_circ_0003998 level was associated with higher serum alpha-fetoprotien (AFP) level (P=0.003), larger tumor diameter (P=0.009), lower differentiation level (P=0.023) and microvascular invasion (P=0.028). The plasma level of hsa_circ_0003998 in HCC patients was significantly higher than those in hepatitis B patients (P<0.001) and healthy controls (P<0.001). Its level was significantly reduced after the operation (P<0.001). The area under the ROC curve (AUC) for distinguishing HCC from adjacent noncancerous tissues was 0.894 (95% CI=0.86-0.922, P<0.001), the sensitivity and specificity were 0.84 and 0.8, respectively. Comparing with hepatitis B patients and healthy controls, hsa_circ_0003998, respectively, had an AUC value of 0.833 (95% CI=0.763-0.889, P<0.001) and 0.892 (95% CI=0.831-0.937, P<0.001). Their sensitivity and specificity were 0.83, 0.7 and 0.8, 0.84, respectively. Moreover, the combination of hsa_circ_0003998 and AFP showed the highest AUC value of 0.947, the sensitivity and specificity were 0.88 and 0.92, respectively. The hsa_circ_0003998 (P=0.003) and AFP (P=0.008) levels were independent prognostic factors for HCC. The overall survival of HCC patients with high level of hsa_circ_0003998 was significantly poorer than those with low level (P=0.005). Conclusion: Our findings suggest that hsa_circ_0003998 may be used as a novel potential biomarker for the diagnosis and prognosis of HCC patients.

5.
Mol Carcinog ; 58(10): 1897-1907, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313392

RESUMO

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Tropomodulina/genética , Animais , Carcinoma Hepatocelular/patologia , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética
6.
Oncol Res ; 27(7): 773-778, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29540256

RESUMO

Luteolin, which is found in plant foods, has a range of therapeutic applications. In order to examine the potential roles of luteolin in ovarian teratocarcinoma, the human ovarian teratocarcinoma cell line PA-1 was selected for functional experiments in vitro and in vivo. We demonstrated that luteolin inhibited the proliferation and colony formation of PA-1 cells in vitro. The flow cytometry results suggested that luteolin induced apoptosis of PA-1 cells in a dose-dependent manner. Immunofluorescence and qRT-PCR results showed that the expression of B-cell lymphoma-2 (Bcl-2) was decreased in luteolin-treated cells, whereas the expression of Bcl-2-associated X (Bax) was increased compared with that in the control group. In addition, luteolin inhibited the tumor growth of ovarian teratocarcinoma cells in a xenograft model. All the results suggested that luteolin induced cell apoptosis and inhibited tumor growth of PA-1 cells.


Assuntos
Luteolina/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Teratoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/patologia , Teratoma/patologia
7.
Oncotarget ; 7(38): 62327-62339, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27694689

RESUMO

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Despite the therapeutic advances that have been achieved during the past decade, the molecular pathogenesis underlying HCC remains poorly understood. In this study, we discovered that increased expression eukaryotic translation initiation factor 5B (eIF5B) was significantly correlated with aggressive characteristics and associated with shorter recurrence-free survival (RFS) and overall survival (OS) in a large cohort. We also found that eIF5B promoted HCC cell proliferation and migration in vitro and in vivo partly through increasing ASAP1 expression. Our findings strongly suggested that eIF5B could promote HCC progression and be considered a prognostic biomarker for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Fatores de Iniciação em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Seguimentos , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Fígado/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Análise Serial de Tecidos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Ethnopharmacol ; 179: 291-300, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26743227

RESUMO

BACKGROUND: Polygonatum kingianum has been used in the prevention and treatment of diabetes, hyperlipidemia and related metabolic syndrome in Asian counties for centuries. In this study, the blood glucose regulation activity and mechanism of total saponins from P. kingianum (TSPK) were investigated in streptozotocin (STZ)-induced diabetic rats in this research. METHODS: TSPK (0.025g/kg and 0.1mg/kg) was administrated by gavage to STZ-induced diabetic rats for 8 weeks. Changes of body weight, food intakes, blood glucose, serum insulin and lipid indexes were observed. Genome-wide expression profiling was applied to explore the gene expression alternation after treated with TSPK. Expressions of adenosine monophosphate activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), the relative transcript level of glucose kinase and glucose-6-phosphatase (GK/G6P) in the liver were investigated. Meanwhile, contents of AMPK, and glucose transporter subtype-4 (GLUT4) in skeletal muscle, and peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue were investigated. RESULTS: TSPK could effectively alleviate hyperglycemia and hyperlipidemia in diabetic rats. Genome-wide expression profiling showed that TSPK up-regulated the expression of GLUT4 while down-regulated the expression of G6P in insulin signal pathway. In the liver, the expression of AMPK and GK are increased. Further more, TSPK promoted the expressions of GLUT4 in skeletal muscle, and PPAR-γ in adipose tissue, respectively. CONCLUSION: These results provide possible mechanisms for the antidiabetic effects of TSPK. TSPK could promote not only glycogenesis but also glucose utilization in peripheral tissue. Our results suggested that TSPK may be used as adjuvant therapy to control blood glucose and insulin resistance in type 2 diabetic individuals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Polygonatum , Saponinas/isolamento & purificação , Saponinas/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Diosgenina , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Glucose-6-Fosfatase/metabolismo , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Lipídeos/sangue , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , PPAR gama/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Ratos , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
9.
PLoS One ; 10(7): e0126566, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26176219

RESUMO

BACKGROUND: Wilms tumor (WT) is an embryonic kidney cancer, for which histone acetylation might be a therapeutic target. LBH589, a novel targeted agent, suppresses histone deacetylases in many tumors. This study investigated the antitumor activity of LBH589 in SK-NEP-1 and G401 cells. METHODS: SK-NEP-1 and G401 cell growth was assessed by CCK-8 and in nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometry detected apoptosis in cell culture. Gene expressions of LBH589-treated tumor cells were analyzed using an Arraystar Human LncRNA Array. The Multi Experiment View cluster software analyzed the expression data. Differentially expressed genes from the cluster analyses were imported into the Ingenuity Pathway Analysis tool. RESULTS: LBH589 inhibited cell proliferation of SK-NEP-1 and G401 cells in a dose-dependent manner. Annexin V, TUNEL and Hochest 33342 staining analysis showed that LBH589-treated cells showed more apoptotic features compared with the control. LBH589 treatment inhibited the growth of SK-NEP-1 xenograft tumors in nude mice. Arraystar Human LncRNA Array analysis of genes and lncRNAs regulated by LBH589 identified 6653 mRNAs and 8135 lncRNAs in LBH589-treated SK-NEP-1 cells. The most enriched gene ontology terms were those involved in nucleosome assembly. KEGG pathway analysis identified cell cycle proteins, including CCNA2, CCNB2, CCND1, CCND2, CDK4, CDKN1B and HDAC2, etc. Ingenuity Pathway Analysis identified important upstream molecules: HIST2H3C, HIST1H4A, HIST1A, HIST1C, HIST1D, histone H1, histone H3, RPRM, HSP70 and MYC. CONCLUSIONS: LBH589 treatment caused apoptosis and inhibition of cell proliferation of SK-NEP-1and G401 cells. LBH589 had a significant effect and few side effects on SK-NEP-1 xenograft tumors. Expression profiling, and GO, KEGG and IPA analyses identified new targets and a new "network" of genes responding to LBH589 treatment in SK-NEP-1 cells. RPRM, HSP70 and MYC may be important regulators during LBH589 treatment. Our results provide new clues to the proapoptotic mechanism of LBH589.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Tumor de Wilms/patologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Camundongos , Camundongos Nus , Panobinostat , RNA Longo não Codificante/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Cancer Res Clin Oncol ; 141(7): 1195-203, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25512078

RESUMO

PURPOSE: To investigate the expression of SRHC and the role of SRHC in the pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched non-tumor liver tissues (controls) collected from 81 patients who underwent hepatectomy in Shanghai, China. The expression levels of SRHC were determined by quantitative reverse-transcription polymerase chain reaction. Statistical analyses were used to associate the levels of SRHC with tumor features and patient outcomes. RESULTS: We found that a lower SRHC expression level was significantly more frequent in tissues with a high serum a-fetoprotein level (positive, >20 µg/L, P = 0.004) and a low degree of differentiated tumors (poorly differentiated, P = 0.017). Furthermore, we found that the promoter region of SRHC contains a CpG-rich island and that SRHC is down-regulated in tumors by DNA methylation. CONCLUSION: Here, we identified a new long noncoding RNA designated as SRHC that is capable of inhibiting cancer proliferation and is down-regulated in tumors at least partly by DNA methylation.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Inativação Gênica , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Metilação de DNA , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
11.
J Cancer Res Clin Oncol ; 140(1): 109-16, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24240726

RESUMO

PURPOSE: To investigate the expression and clinical significance of CADM2 in hepatocellular carcinomas (HCC). METHODS: The level of expression of CADM2 mRNA was assessed in frozen tumor specimens and adjacent noncancerous tissues from 30 HCC patients by real-time PCR. The protein level was determined by immunohistochemistry on a tissue microarray containing tumor and adjacent noncancerous tissues from 234 HCC patients. Clinicopathological characteristics associated analysis was performed through SPSS18 . RESULTS: CADM2 was strikingly down regulated in HCC. CADM2 expression was associated with differentiation (P = 0.000), serum alpha-fetoprotein (P = 0.003), vascular invasion (P = 0.001), and hepatitis B surface antigen (HBsAg, P = 0.038). Furthermore, patients with low CADM2 expression had significantly poorer recurrence-free survival (RFS) (40.8 and 34.2 % vs. 56.3 and 50.1 % in 3- and 5-year RFS, respectively, P = 0.005). Subgroup analysis revealed that the difference in RFS between groups with low- and high-CADM2 expression still existed among patients belonging to stage 0 or A of BCLC staging system (P = 0.008), patients with tumor ≤5 cm in size (P = 0.013), and alpha-fetoprotein-negative patients (P = 0.003). Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.007). Further multivariate Cox regression analysis indicated that CADM2 expression level, tumor size, tumor number, vascular invasion, HBsAg were independent risk factors for HCC recurrence. CONCLUSION: CADM2 serves as a novel predictor of RFS in HCC patients after curative resection.


Assuntos
Carcinoma Hepatocelular/metabolismo , Moléculas de Adesão Celular/biossíntese , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia/metabolismo , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Moléculas de Adesão Celular/genética , Regulação para Baixo , Feminino , Hepatectomia , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise Serial de Tecidos
12.
J Exp Clin Cancer Res ; 31: 92, 2012 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-23140181

RESUMO

BACKGROUND: Leukemia, a heterogeneous clonal disorder of hematopoietic progenitor cells, presents a world-wide health problem, especially in childhood. F1F0 ATPase, an inner mitochondrial enzyme, is expressed on the plasma membrane of tumor cells, and its inhibition induces both anti-angiogenic and anti-tumorigenic activity. METHODS: Monoclonal Antibody (McAb) against ATPase was produced by polyethylene glycol-mediated fusions and screened by ELISA. Proliferation, cell cycle and apoptosis of cells were analyzed when the surface ATPase of cells was blockaded with McAb. RESULTS: We detected cell-membrane expression of the F1F0 ATPase ß subunit on 0.1% to 56% of the 11 cell lines derived from leukemia, including acute myeloid leukemia (AML). We produced a monoclonal antibody, McAb7E10, which recognizes both the native and recombinant ATPase ß subunit, with a dissociation constant (KD) of 3.26E-10. We demonstrate that McAb7E10 binds to ATPase at the cell surface, where it is able to inhibit ATP synthesis. McAb7E10 significantly inhibited proliferation of AML cell lines in vitro: the relative inhibitory rates of 50 µg/mL McAb7E10 treated MV4-11and HL-60 cells were 69.6% and 81.9% respectively. Cell cycle analysis indicated that McAb7E10 significantly induced apoptosis in MV4-11 and HL-60 cells: the relative rates of apoptosis in 5, 10 and 50ug/mL McAb7E10 treated MV4-11 cells was 3.6 ± 0.83%, 8.4 ± 1.69% and 17.3 ± 2.56% compared to 1.5% ± 0.85% in mouse IgG treated cells (p < 0.01). The relative rate of apoptosis in 5, 10 and 50ug/mL McAb7E10 treated HL-60 cells was 5.5 ± 2.37%, 11.3 ± 3.62% and 19.9 ± 3.31% compared to 1.56% ± 0.97% in mouse IgG treated cells (p < 0.01). Annexin V staining demonstrated that the relative apoptotic rates in 50 µg/mL McAb7E10 treated MV4-11 and HL-60 cells were 50.5% ± 7.04% and 32.9% ± 4.52%, respectively, significantly higher than IgG control antibody treated cells were 21.9% ± 3.11% and 15.3% ± 3.95%, p < 0.01. CONCLUSIONS: These findings indicate that ectopic expression of ATPase ß subunit may be a tumor-associated antigen in hematological malignancies. The F1F0 ATPase ß subunit provides a potential target for immunotherapy in AML and hematological malignancies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda , ATPases Mitocondriais Próton-Translocadoras , Animais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , ATPases Mitocondriais Próton-Translocadoras/imunologia , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/imunologia
13.
Cancer Cell Int ; 12(1): 40, 2012 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-22958424

RESUMO

BACKGROUND: The Real-time PCR Array System is the ideal tool for analyzing the expression of a focused panel of genes. In this study, we will analyze the gene expression profile of pediatric acute myeloid leukemia with real-time PCR arrays. METHODS: Real-time PCR array was designed and tested firstly. Then gene expression profile of 11 pediatric AML and 10 normal controls was analyzed with real-time PCR arrays. We analyzed the expression data with MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profile derived from cluster analyses were imported into the Ingenuity Pathway Analysis Tool. RESULTS: We designed and tested 88 real-time PCR primer pairs for a quantitative gene expression analysis of key genes involved in pediatric AML. The gene expression profile of pediatric AML is significantly different from normal control; there are 19 genes up-regulated and 25 genes down-regulated in pediatric AML. To investigate possible biological interactions of differently regulated genes, datasets representing genes with altered expression profile were imported into the Ingenuity Pathway Analysis Tool. The results revealed 12 significant networks. Of these networks, Cellular Development, Cellular Growth and Proliferation, Tumor Morphology was the highest rated network with 36 focus molecules and the significance score of 41. The IPA analysis also groups the differentially expressed genes into biological mechanisms that are related to hematological disease, cell death, cell growth and hematological system development. In the top canonical pathways, p53 and Huntington's disease signaling came out to be the top two most significant pathways with a p value of 1.5E-8 and2.95E-7, respectively. CONCLUSIONS: The present study demonstrates the gene expression profile of pediatric AML is significantly different from normal control; there are 19 genes up-regulated and 25 genes down-regulated in pediatric AML. We found some genes dyes-regulated in pediatric AML for the first time as FASLG, HDAC4, HDAC7 and some HOX family genes. IPA analysis showed the top important pathways for pediatric AML are p53 and Huntington's disease signaling. This work may provide new clues of molecular mechanism in pediatric AML.

14.
Artigo em Chinês | MEDLINE | ID: mdl-22263493

RESUMO

We established and perfected the system of control work, achieved the expected targets, and explored the advisable pattern for prevention and control on soil-transmitted nematode diseases. To perform the prevention and control on soil-transmitted nematodiasis, there should be the guidance of government, the multi-sectoral cooperation, community participation, paying attention to the organization and management, and highlighting the key points including education and deworming.


Assuntos
Doenças Parasitárias/prevenção & controle , China , Educação em Saúde , Humanos , Doenças Parasitárias/tratamento farmacológico , Saneamento
15.
Artigo em Chinês | MEDLINE | ID: mdl-22263501

RESUMO

OBJECTIVE: To evaluate the effect of comprehensive intervention measures to control and prevent parasitic diseases in the demonstration plot of Xiangyun County, so as to provide the evidence for establishing appropriate measures of parasitic diseases control and prevention. METHODS: The baseline data of soil-transmitted nematode infections were obtained in 2006. A series of intervention measures, including health education, deworming, drinking water improvement,latrine improvement, and environment reconstruction, were performed for three years and the effect of the comprehensive intervention measures was evaluated by the national expert group in 2009. RESULTS: The awareness rate of parasitic disease knowledge of residents in 2009 (86.96%) was significantly higher than that in 2006 (35.20%) (Chi2 = 122.95, P < 0.01). The passing rate of resident health behavior in 2009 (97.10%) was significantly higher than that in 2006 (48.00%) (Chi2 = 122.95, P < 0.01). The general infection rate of parasites in 2009 (2.47%) was significantly lower than that in 2006 (19.14%) (Chi2 = 162.88, P < 0.01). Of soil-transmitted nematode infections, the infection rates of Ascaris lumbricoides in both 2006 and 2009 were the highest and the rates were 18.74% and 2.08%, respectively. CONCLUSIONS: In the demonstration plots for parasitic diseases control and prevention of Xiangyun County, the effect of the comprehensive intervention measures which take health education as the forerunner and give priority to control source of parasite infection is remarkable. The measures implemented can achieve the purpose to reduce the infection rates of parasites and improve human health.


Assuntos
Doenças Parasitárias/prevenção & controle , China/epidemiologia , Feminino , Educação em Saúde , Humanos , Masculino , Doenças Parasitárias/epidemiologia
16.
EMBO J ; 28(18): 2719-32, 2009 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-19696742

RESUMO

We here report that miR-17-92 cluster is a novel target for p53-mediated transcriptional repression under hypoxia. We found the expression levels of miR-17-92 cluster were reduced in hypoxia-treated cells containing wild-type p53, but were unchanged in hypoxia-treated p53-deficient cells. The repression of miR-17-92 cluster under hypoxia is independent of c-Myc. Luciferase reporter assays mapped the region responding to p53-mediated repression to a p53-binding site in the proximal region of the miR-17-92 promoter. Chromatin immunoprecipitation (ChIP), Re-ChIP and gel retardation assays revealed that the binding sites for p53- and the TATA-binding protein (TBP) overlap within the miR-17-92 promoter; these proteins were found to compete for binding. Finally, we show that pri-miR-17-92 expression correlated well with p53 status in colorectal carcinomas. Over-express miR-17-92 cluster markedly inhibits hypoxia-induced apoptosis, whereas blocked miR-17-5p and miR-20a sensitize the cells to hypoxia-induced apoptosis. These data indicated that p53-mediated repression of miR-17-92 expression likely has an important function in hypoxia-induced apoptosis, and thus further our understanding of the tumour suppressive function of p53.


Assuntos
Apoptose , MicroRNAs/genética , Família Multigênica , Proteína Supressora de Tumor p53/genética , Sítios de Ligação , Células CACO-2 , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Humanos , Hipóxia , Cinética , Luciferases/metabolismo , Modelos Biológicos , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
J Clin Gastroenterol ; 43(9): 831-7, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19461527

RESUMO

GOALS: To gain an insight into the putative role of annexin A5 (ANXA5) in the tumor stage and its clinical outcome. BACKGROUND: ANXA5 is a calcium-binding protein, which has been implicated in the carcinogenesis of several carcinomas. However, the role of ANXA5 in colorectal cancer (CRC) is unclear. STUDY: We investigated the expression of ANXA5 in colorectal adenocarcinoma. This study included 207 consecutive patients with sporadic CRC. Paired colorectal tissue samples and corresponding nonmalignant tissues were obtained by surgical resection. ANXA5 mRNA and protein expression in each tissue were assessed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical staining. Data were statistically correlated with pathologic parameters and clinical outcome. RESULTS: Real-time reverse transcriptase polymerase chain reaction showed that there is an up-regulation in the mRNA level of ANXA5 in tumors (P<0.001). Immunohistochemical study revealed that high ANXA5 expression was present in 40.58% (84 of 207) of tumors. Univariate analysis showed increased ANXA5 expression correlated with pT stage (P=0.008), liver metastasis (P=0.024), pathologic tumor-node-metastasis stage (P=0.015), Dukes' stage (P=0.017), recurrence (P=0.024), cancer-related death (P=0.028), recurrence-free probability (P=0.003), and overall survival (P=0.005). Multivariate analysis showed that ANXA5 expression and liver metastasis significantly correlated with recurrence-free probability (P=0.039 and P=0.048, respectively) and overall survival (P=0.012 and P=0.021, respectively) independent of pT stage and pN stage. CONCLUSIONS: From these findings ANXA5 expression seems to be related to the tumor stage and clinical outcome of CRC. Thus ANXA5 could serve as a prognostic marker for tumor progression.


Assuntos
Adenocarcinoma/química , Anexina A5/análise , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Idoso , Anexina A5/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/química , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
18.
Int J Biochem Cell Biol ; 40(10): 2151-63, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18378486

RESUMO

Annexins are a family of calcium-dependent phospholipid-binding proteins that have been proposed to be involved in a wide range of important biological processes. At present, only a few annexins have been identified in parasites, and the physiological roles of these annexins are obscure. Earlier, we cloned a novel annexin (annexin B1) from Taenia solium metacestodes and found that annexin B1 was detectable in the surrounding host-derived layer with granulomaous infiltration. The objective of this study was to investigate the secretion and physiological function of annexin B1. We expressed a green fluorescent protein-tagged annexin B1 (GFP-anxB1) in living SiHa cells and showed that it was secreted upon stimulation with dexamethasone (Dex). This secretion was not inhibited by brefeldin A but was blocked by pre-treatment with the intracellular calcium-specific chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Furthermore, we describe for the first time that annexin B1 can bind to the extracellular surface of human eosinophils and produce Ca(2+)-influx. The Ca(2+)-influx induced apoptosis in eosinophils, which was inhibited by pre-loading the Ca(2+) channel blocker 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-metho-xyphenethyl]-1H-imidazole, HCl (SKF-96365). In conclusion, these findings represent direct and substantial evidence for the secretion of annexin B1 by living cells; the apoptosis in eosinophil induced by annexin B1 might be a novel strategy for T. solium metacestodes to prevent the host's immune attack.


Assuntos
Anexinas/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/farmacologia , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Taenia solium/metabolismo , Animais , Brefeldina A/farmacologia , Calcimicina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Citocromos c/metabolismo , Dexametasona/farmacologia , Eosinófilos/enzimologia , Exocitose/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Humanos , Modelos Biológicos , Ligação Proteica/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo
19.
Cancer Sci ; 99(4): 770-80, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18307539

RESUMO

China has the largest numbers of hereditary non-polyposis colorectal cancer (HNPCC) patients based on its population of 1.4 billion. However, the clinical data and mismatch repair (MMR) gene analyses have been limited. Here we performed microsatellite instability (MSI) and immunohistochemistry (IHC) analyses on a series of patients with a high-risk for HNPCC: 61 patients with family histories fulfilling Amsterdam criteria II (ACII-HNPCC) or suspected HNPCC criteria (S-HNPCC), and 106 early onset colorectal cancer (CRC) patients. Sixty late-onset CRC patients were used as control. Methylation of the hMLH1 promoter was analyzed on tumors lacking hMLH1 expression. MMR germ-line mutations were screened on patients with tumors classified as MSI-H/L or negative for IHC. We identified 27 germ-line MMR variants in the 167 patients with a high-risk for HNPCC while only one germ-line mutation in hMSH6 was found in the late-onset CRC group. Of those, 23 were pathogenic mutations. The high incidence of gastric and hepatobiliary cancers coupled with the increasing number of small families in China reduces the sensitivity (43.5%, 30.4%) and positive predictive value (PPV) (45.5%, 17.9%) of the ACII- or S-HNPCC criteria. MSI or IHC testing are highly sensitive in detecting pathogenic mutations (sensitivities = 91.3% and 95.6%, respectively), but the PPVs are quite low (25.6% and 27.8%, respectively). Considering that all 12 tumors with pathogenic mutations in hMLH1 also showed promoter unmethylation, the sensitivity of IHC in conjunction with hMLH1 promoter methylation analysis is not reduced, but the PPV was increased from 27.8% to 61.1%, and the total cost was greatly reduced.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Testes Genéticos/métodos , Proteínas Nucleares/genética , Adulto , China , Análise Custo-Benefício , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Testes Genéticos/economia , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Regiões Promotoras Genéticas
20.
Cell Biol Int ; 32(1): 121-7, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17936648

RESUMO

Annexin B1 is a novel member of the annexin superfamily which was isolated from a Cysticercus cellulosae cDNA library. To investigate the physiological roles of annexin B1, we firstly performed immunohistochemical analysis on frozen Cysticercus cellulosae sections and found that annexin B1 was present not only in the tegument of the bladder wall, but also in the host-derived inflammatory layer; In addition, ELISA analysis revealed that annexin B1 could be detected in the cystic fluid of Cysticercus cellulosae and the sera of pigs with cysticercosis. These findings indicated that annexin B1 might be a secretary protein. We further constructed a pEGFP-annexin B1 plasmid and transfected it into SiHa cells. We found that GFP-annexin B1 was stimulated to translocate to the plasma membrane by phorbol 12-myristate 13-acetate (PMA). By contrast, it was induced to distribute at the plasma and nuclear membranes by treatment with calcium ionophore ionomycin. PMA increased annexin B1 membrane binding, which might facilitate exocytosis. Moreover, translocation of the protein to the plasma and nuclear membranes after stimulated by ionomycin, was predicted to be related to an additional function.


Assuntos
Anexinas/metabolismo , Proteínas de Helminto/metabolismo , Ionomicina/farmacologia , Ésteres de Forbol/farmacologia , Animais , Cálcio/metabolismo , Cisticercose/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Suínos , Taenia solium/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo
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