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1.
Cancer Med ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31851786

RESUMO

BACKGROUND: Definitive chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients have demonstrated great variations in their responses to dCRT and inevitably progressed following treatment. METHODS: To identify prognostic biomarkers, we performed targeted next-generation sequencing of 416 cancer-related genes on primary tumors from 47 nonsurgical ESCC patients prior to dCRT treatment. The association between genetic alterations and patients' local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS: TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%). Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08-0.77, P = .015) and progression-free survival (PFS) (HR, 0.35; 95%CI, 0.13-0.93, P = .030) following dCRT. Meanwhile, YAP1 amplification (n = 7) was an adverse prognostic factor, and patients with this alteration demonstrated a tendency toward worse outcomes with shorter LRFS (HR, 4.06; 95%CI, 1.26-13.14, P = .019) and OS (HR, 2.78; 95%CI, 0.95-8.17, P = .062). In a subgroup analysis, while sex and M-stage were controlled, a much stronger negative effect of YAP1 amplification vs wild-type in LRFS was observed (log-rank P = .0067). CONCLUSION: The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored.

2.
Oncol Rep ; 42(5): 2130-2138, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545474

RESUMO

It has been reported that NF­κB activating protein (NKAP) is a transcriptional repressor of the Notch signaling pathway and is involved in the proliferation and survival of hematopoietic stem cells. In the present study, we aimed to investigate the effect of NKAP on the progression and metastasis of colon cancer. The results of immunohistochemical staining and western blot analysis showed that NKAP was upregulated in colon cancer tissues, and its expression was associated with colon cancer stages. CCK­8, colony formation, Transwell, and flow cytometry assays were used to demonstrate that NKAP knockdown significantly suppressed the proliferation and invasion of HCT116 and HT­29 cells, and also induced apoptosis and autophagy. By contrast, NKAP overexpression markedly promoted the proliferation and invasion of HCT­15 cells, and inhibited cell apoptosis and autophagy. Moreover, we observed that NKAP knockdown inhibited the epithelial­mesenchymal transition (EMT) process in HCT116 and HT­29 cells, while NKAP overexpression promoted EMT in HCT­15 cells. Furthermore, NKAP knockdown inhibited activation of the Akt/mTOR signaling pathway by downregulating the phosphorylation of Akt and mTOR, as well as their downstream proteins, whereas NKAP overexpression promoted the Akt/mTOR signaling pathway. Additionally, expression of P65 was downregulated by silencing of NKAP and upregulated by NKAP overexpression. These data suggest that NKAP functions as an oncogene in the growth and invasion of colon cancer in vitro.

3.
Medicine (Baltimore) ; 98(30): e16439, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348245

RESUMO

BACKGROUND: We performed the meta-analysis to evaluate the overall safety of programmed cell death-1 (PD-1) or ligand 1 (PD-L1) inhibitor treatment for lung cancer patients. METHOD: Randomized controlled trials were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Risk ratio (RR) of PD-1/PD-L1 inhibitor treatment-related death, treatment-related adverse events, any serious events, and any events leading to discontinuation were all taken into account for the final evaluation. RESULTS: Fourteen studies were collected for the meta-analysis. The RR of treatment-related death for PD-1/PD-L1 was significantly lower than that of the control group (RR = 0.37, 95% confidence interval, CI: [0.21, 0.66]). Similar analysis results could also be seen for the RR of treatment-related adverse events and adverse events leading to discontinuation. When PD-1/PD-L1 was combined with chemotherapy, it increased the RR of adverse events leading to discontinuation (RR = 1.68, 95% CI: [1.22, 3.32]). The RR of overall treatment-related adverse events was lower in nivolumab (PD-1) than that of the control group (nivolumab + ipilimumab) (RR = 0.77, 95% CI: [0.65, 0.90]). Similar analysis results could also be seen in the RR of treatment-related adverse events for grade 3 to 5 and adverse events leading to discontinuation. CONCLUSION: Compared with chemotherapy, RR of the treatment-related deaths associated with PD-1/PD-L1 inhibitor was significantly lower than that of the chemotherapy group, while it did not increase the RR when they were combined with chemotherapy or other drugs. When PD-1/PD-L1 was combined with chemotherapy, it increased the RR of adverse events leading to discontinuation.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Neoplasias Pulmonares/mortalidade , Gradação de Tumores , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida
4.
Medicine (Baltimore) ; 98(19): e15582, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083238

RESUMO

BACKGROUND: We designed the study to investigate whether methotrexate, doxorubicin, and cisplatinum (MAP) chemotherapy strategy was still the preferred option for the survival of osteosarcoma patients. METHOD: We collected some trials of osteosarcoma to make a meta-analysis first. Then, we retrospectively collected data from 115 patients with osteosarcoma and performed further analysis to verify the impact of MAP regimen on the survival of patients. RESULTS: Seven studies including 3433 participants met the preliminary inclusion criteria. Meta-analysis of the 3-year disease-free survival (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 0.88-1.28; P = .52) and overall survival (OR = 1.21, 95% CI: 0.70-2.11; P = .54), 5-year disease-free survival (OR = 1.07, 95% CI: 0.87-1.30; P = .54) and overall survival (OR = 0.86, 95% CI: 0.65-1.12; P = .26), and mortality rate (OR = 0.90, 95% CI: 0.70-1.17; P = .44), showed no statistically significant differences. The most common grade 3/4 adverse events were neutropenia (498 [85.9%] patients in MAP vs 533 [93.3%] in MAP plus ifosfamide and etoposide, or other adjuvant therapy drugs [MAP]). MAP was associated with less frequent toxicities than MAP group with statistical significance in thrombocytopenia, febrile neutropenia, anemia, and hypophosphatemia. The same phenomenon could also be seen in the analysis of clinical data. CONCLUSION: MAP regimen remains the preferred option for osteosarcoma chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Metotrexato/uso terapêutico , Osteossarcoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias Ósseas/mortalidade , Cisplatino/efeitos adversos , Doxorrubicina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Osteossarcoma/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
5.
Cell Mol Immunol ; 10(2): 176-82, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23416968

RESUMO

Osteopontin (OPN), a multifunctional glycoprotein, has three transcripts that have distinct roles in tumors in vitro. Whether OPN transcripts have different functions in tumor processes in vivo is unclear. It has been reported that immune cell-derived OPN can promote tumor formation. We propose a hypothesis that tumor-derived OPN may facilitate tumor immune escape by affecting immune cell differentiation and function. In this study, we constructed lentiviral expression vectors of OPN transcripts and transfected them into the MCF-7 cell line. MCF-7 cells transfected with OPN transcripts were injected into the armpit of nude mice, and tumor growth was monitored. The results showed that all OPN transcripts promoted local tumor formation, but that there was no significant difference among transcripts. We also investigated the effect of the OPN expressed by tumor cells on monocyte differentiation by coculturing monocytes with tumor supernatant. We found OPN-c upregulated CD163 levels compared with OPN-a and OPN-b; however, none of the transcripts affected HLA-DR and CD206 levels. All OPN transcripts significantly inhibited TNF-α and enhanced IL-10 production by monocytes. Furthermore, we found that the overexpression of OPN transcripts significantly upregulated TGF-ß1 and MCP-1 production by tumor cells. Using neutralizing antibody and recombinant cytokines, we found that OPN overexpressed by tumor cells regulates the production of TNF-α and IL-10 by monocytes partly via MCP-1 and TGF-ß1, respectively. Collectively, our results show that OPN transcripts have no distinct role in breast cancer formation in vivo. We also demonstrate that OPN regulates the alternative activation of monocytes via TGF-ß1 and MCP-1, which may represent an additional mechanism for tumor immune escape.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Quimiocina CCL2/fisiologia , Monócitos/imunologia , Osteopontina/genética , Processamento de RNA/imunologia , Fator de Crescimento Transformador beta1/fisiologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Variação Genética/imunologia , Humanos , Evasão da Resposta Imune/genética , Camundongos , Camundongos Nus , Monócitos/metabolismo , Monócitos/patologia , Osteopontina/biossíntese , Processamento de RNA/genética
6.
Blood ; 119(20): 4636-44, 2012 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-22415751

RESUMO

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. Furthermore, dendritic cells matured in the presence of TIMP-3 could stimulate allogeneic naive T helper (Th) cells to display a prominent Th2 polarization. Importantly, in an autoimmune disorder-primary immune thrombocytopenia, TIMP-3 showed a statistically positive correlation with IL-4 and platelet count, but a negative correlation with IFN-γ in patient blood samples. Collectively, these in vitro and in vivo data clearly suggested a novel role of TIMP-3 in Th1/Th2 balance in humans.


Assuntos
Polaridade Celular/genética , Células Dendríticas/fisiologia , Células Th1/fisiologia , Células Th2/fisiologia , Inibidor Tecidual de Metaloproteinase-3/fisiologia , Adolescente , Adulto , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/fisiologia , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/metabolismo , RNA Interferente Pequeno/farmacologia , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Inibidor Tecidual de Metaloproteinase-3/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Adulto Jovem
7.
Gene ; 486(1-2): 74-80, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21801820

RESUMO

RhoBTB2 was isolated recently as a tumor suppressor gene from sporadic breast cancer. Although RhoBTB2 was found to be frequently lost in breast cancer and a variety of cancers, its antitumor effect, however, remains unclear. In this study, we constructed a recombinant expression vector pEGFP-N1-RhoBTB2 and transfected it into RhoBTB2-negative breast tumor cell line T-47D. Stable transformanted cells were identified by fluorescence microscope, RT-PCR and Western blot. Cell viability was measured by MTT assay. Colony forming efficiency of breast tumor cells was detected by colony formation assay. Morphological change of apoptotic cells was observed by hematoxylin-eosin staining. Apoptotic ratio was determined by flow cytometry. Cell invasion and migration ability assay were performed using transwell system. Overexpression of RhoBTB2 in breast tumor cells significantly inhibited the proliferation and colony formation of tumor cells. In addition, RhoBTB2 also elevated the apoptotic ratio and caused typical changes of apoptotic morphology in breast tumor cells of RhoBTB2 overexpression. But RhoBTB2 did not influence the invasion and migration ability of breast tumor cells. Therefore, RhoBTB2 is an important tumor suppressor gene related with breast cancer and may play antitumor roles by inhibiting proliferation, preventing colony formation and promoting the apoptosis of tumor cells. However, the precise mechanism behind the antitumor effects of RhoBTB2 needs to be investigated further.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Proteínas de Ligação ao GTP/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Apoptose/genética , Apoptose/fisiologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células , Feminino , Proteínas de Ligação ao GTP/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfecção , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/genética , Regulação para Cima
8.
J Clin Immunol ; 31(4): 606-14, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21556937

RESUMO

BACKGROUND: T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled. MATERIALS AND METHODS: CD4(+)IFNγ(-)IL17(-)IL-22(+) T cells (Th22 cells), CD4(+)IFNγ(-)IL-22(-)IL17(+) T cells (pure Th17 cells), CD4(+)IL17(+) T cells (Th17 cells), and CD4(+)IFNγ(+) T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay. RESULTS: Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score. CONCLUSION: Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA.


Assuntos
Artrite Reumatoide/imunologia , Interleucinas/sangue , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/imunologia , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Antígenos CD4/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Interferon gama/sangue , Interleucina-17/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Osteoartrite/imunologia , Células Th1/imunologia
9.
J Gastroenterol Hepatol ; 26(10): 1519-26, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21557772

RESUMO

BACKGROUND AND AIM: A new subset of Treg cells, CD4(+) CD69(+) CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC). METHODS: We detected CD4(+) CD69(+) CD25(-) T cells and its expression of CCR6 and transforming growth factor-ß1 (TGF-ß1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+) CD69(+) CD25(-) T cells in HCC tissues were also analyzed. RESULTS: CD4(+) CD69(+) CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% ± 0.42% vs 4.55% ± 0.33% and 5.15% ± 0.36%, P < 0.0001). The percentage of peripheral CD4(+) CD69(+) CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+) CD69(+) CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-ß1 positive cells in CD4(+) CD69(+) CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+) CD69(+) CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+) CD69(+) CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients. CONCLUSIONS: Increased CD4(+) CD69(+) CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Carcinoma Hepatocelular/imunologia , Subunidade alfa de Receptor de Interleucina-2/análise , Lectinas Tipo C/análise , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Contagem de Linfócito CD4 , Carcinoma Hepatocelular/secundário , Distribuição de Qui-Quadrado , China , Progressão da Doença , Citometria de Fluxo , Humanos , Modelos Lineares , Neoplasias Hepáticas/patologia , Metástase Linfática , Invasividade Neoplásica , Estadiamento de Neoplasias , Fenótipo , Receptores CCR6/análise , Fator de Crescimento Transformador beta1/análise , Carga Tumoral
10.
Cancer Sci ; 102(7): 1264-71, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21443538

RESUMO

The chemokine receptor CCR4 is preferentially expressed on certain immune cells and some hematological tumor cells, which play pivotal roles in suppression of host immune response. However, the reasons for the upmodulation of CCR4 and its immune functions in solid tumors remain unclear. Herein, we aimed to determine the expression profiles of CCR4 in gastric cancer cells and its role in regulating antitumor immunity. CCR4 expression was assessed in 63 cases of gastric carcinomas by immunohistochemistry. We found cancer cells in lymphocyte-rich carcinomas more frequently showed moderate to strong positive staining for CCR4 than those in conventional carcinomas (P = 0.041), and also found a positive relationship between expression of CCR4 and tumor necrosis factor-α (P = 0.012). Stimulation of gastric cell lines with various cytokines showed that tumor necrosis factor-α uniquely upmodulated CCR4 expression through activation of nuclear factor-κB. Additional coculture experiments showed the forced expression of CCR4 in SGC-7901 cells caused a significant reduction of γ-interferon and elevation of interleukin-10 secretion in the supernatants from cocultured SGC-7901 cells and PBMCs. In addition, granzyme A production in cancer cell-cocultured CD56(+) natural killer cells was significantly downregulated. Inhibition of the overexpressed CCR4 in cancer cells by an inhibitor of CCR4, compound 39, proved to partly restore the antitumor immunity in respect of the inverse changes in those factors. Our studies suggest that the aberrant expression of CCR4 in human gastric cancer could contribute to tumor-induced immunosuppression. Conceivably, downmodulation of CCR4 expression could be a promising immunotherapy for human gastric cancer.


Assuntos
Tolerância Imunológica , Receptores CCR4/fisiologia , Neoplasias Gástricas/imunologia , Adulto , Idoso , Feminino , Granzimas/análise , Humanos , Interleucina-10/biossíntese , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Receptores CCR4/análise , Fator de Necrose Tumoral alfa/farmacologia
11.
Immunol Cell Biol ; 88(2): 165-71, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19841638

RESUMO

Hypoxia is a common characteristic of many pathological and physiological conditions that can markedly change cellular metabolism and cause the accumulation of extracellular adenosine. Recent studies have shown that adenosine can modulate the function of certain immune cell types through binding with different adenosine receptors. Our previous studies have shown that hypoxia has an effect on the biological activity of dendritic cells (DCs) by inducing their differentiation towards a Th2 polarising phenotype. However, the mechanisms underlying this suppression remain unclear. In this study, we have demonstrated that hypoxic mDCs predominantly express adenosine receptor A2b. The A2b receptor antagonist MRS1754 was able to increase the production of IL-12p70 and TNF-alpha by hypoxic mDCs and elevate the amount of Th1 cytokine IFN-gamma production in a mDCs-T-cell co-culture system. We also found that the effect of hypoxia on IL-12p70 production was mediated via increased intracellular cAMP levels through the up-regulation of A2b adenosine receptor and the preferential expression of adenosine A2b receptors in hypoxic mDCs was HIF-1 alpha dependent. Therefore, the hypoxic mDCs could provide a useful tool for researching the function of A2bR in human DCs. Our results offer new insights into understanding the molecular mechanisms underlying the biological activities of DCs in local-tissue hypoxic microenvironments.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ativação Linfocitária/imunologia , Receptor A2B de Adenosina/metabolismo , Células Th2/citologia , Células Th2/imunologia , Antagonistas do Receptor A2 de Adenosina , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/imunologia , Polaridade Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Interleucina-12/biossíntese , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Fenótipo , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/genética , Receptor A3 de Adenosina/genética , Receptor A3 de Adenosina/metabolismo , Células Th2/efeitos dos fármacos
12.
Inflamm Res ; 59(4): 271-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19774448

RESUMO

OBJECTIVE: To investigate the effect of fucoidan on the expression of matrix metalloproteinase-9 (MMP-9) from monocytes. METHODS: Human monocytic cell line U937 was purchased from ATCC. During the experiment, FBS-free 1640 was used and U937 was cultivated with 20 ng/ml TNF-alpha and/or different concentrations of fucoidan for 24 h. RT-PCR experiments were used to determine the MMP-9 mRNA expression. ELISA and gelatin zymography detected MMP-9 amounts and activity in the supernatant. The intracellular level of MMP-9 was assayed by Western blot, and the level of CD44 on the surface was assayed by FACS. RESULTS: In this study, we showed that pro-inflammatory cytokine TNF-alpha up-regulated U937 MMP-9 mRNA and protein levels (P < 0.05). Fucoidan can increase the TNF-alpha-induced MMP-9 secretion from U937 (P < 0.05), but no significant difference was observed in MMP-9 mRNA. The intracellular level of MMP-9 treated with TNF-alpha and fucoidan was lower (P < 0.05) than that treated with TNF-alpha alone. In addition, we demonstrated that fucoidan downregulated the surface level of CD44, the main molecule to which MMP-9 attaches. CONCLUSIONS: We demonstrated that fucoidan post-translationally regulated MMP-9 secretion from U937. Reduced intracellular level and decreased membrane attachment may contribute to the increase in MMP-9 secretion.


Assuntos
Antineoplásicos/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Polissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Anticorpos Monoclonais/farmacologia , Western Blotting , Meios de Cultura , Regulação para Baixo/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Indicadores e Reagentes , RNA/biossíntese , RNA/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética/efeitos dos fármacos , Células U937
13.
Cell Mol Immunol ; 7(1): 77-82, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20029460

RESUMO

Hypoxia is a major characteristic of the tumor microenvironment, and its effects on immune cells are proposed to be important factors for the process of tumor immune escape. It has been reported that hypoxia affects the function of dendritic cells and the antitumor function of T cells. Here we discuss the effects of hypoxia on T-cell survival. Our results showed that hypoxia induced apoptosis of T cells. Adenosine and adenosine receptors (AR) are important to the hypoxia-related signaling pathway. Using AR agonists and antagonists, we demonstrated that hypoxia-induced apoptosis of T cells was mediated by A(2a )and A(2b) receptors. Furthermore, we are the first, to our knowledge, to report that hypoxia significantly inhibited the expression of chemokine C receptor 7 (CCR7) of T cells via the A(2)R signal pathway, perhaps representing a mechanism of hypoxia-induced apoptosis of T cells. Collectively, our research demonstrated that hypoxia induces T-cell apoptosis by the A(2)R signaling pathway partly by suppressing CCR7. Blocking the A(2)R signaling pathway and/or activation of CCR7 can increase the anti-apoptosis function of T cells and may become a new strategy to improve antitumor potential.


Assuntos
Apoptose , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Receptores CCR7/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Hipóxia Celular , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/imunologia , Receptor A2B de Adenosina/genética , Receptor A2B de Adenosina/imunologia , Transdução de Sinais , Linfócitos T/metabolismo
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