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1.
Pathol Oncol Res ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31642035

RESUMO

Long noncoding RNAs (lncRNAs) play important roles in regulating the apoptosis of gastric cancer (GC) cells. This study aims to investigate the underlying mechanism of lncRNA CASC9 in regulating the apoptosis of GC cells. The expressions of lncRNA and protein in GC tissues and cell lines were detected by qRT-PCR and western blot. GC cell apoptosis was detected by flow cytometry analysis. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to verify the interaction between CASC9 and BMI1. LncRNA CASC9 was upregulated in GC tissue and GC cells, and high CASC9 expression was positively correlated with TNM stage and lymph node metastasis. Silencing CASC9 promoted the apoptosis of GC cells. LncRNA CASC9 could interact with BMI1 and positively regulate BMI1 expression. Silencing CASC9 promoted the ubiquitination of BMI1. In addition, lncRNA CASC9 regulated the apoptosis of GC cells through BMI1. Furthermore, interfering CASC9 inhibited the tumor growth of GC. LncRNA CASC9 could interact with BMI1 to regulate the degradation of BMI1, thus to affect the apoptosis of GC cells and suppressed tumor growth.

2.
Leukemia ; 33(10): 2454-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30953029

RESUMO

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

3.
J Laparoendosc Adv Surg Tech A ; 28(11): 1294-1297, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30106603

RESUMO

OBJECTIVE: Short-term complications and long-term prognoses of three kinds of digestive tract reconstructions after radical gastrectomy for distal gastric cancer were compared. MATERIALS AND METHODS: Patients who underwent radical gastrectomy for distal gastric cancer were divided into three groups according to the type of digestive tract reconstruction: Billroth I, Billroth II, and Roux-en-Y anastomosis. Clinicopathological characteristics, intraoperative conditions, short-term complications, and long-term prognoses were compared among the three groups. RESULTS: There were no significant differences in the clinicopathological characteristics and postoperative complications among the three groups (P > .05). There was no significant difference in the operative times of the Billroth I and Billroth II anastomosis groups, but the operative times in both groups were shorter than the operative time in the Roux-en-Y anastomosis group (P < .05). The 5-year overall survival (OS) rate in the Billroth I, Billroth II, and Roux-en-Y anastomosis groups was 58.3%, 55.0%, and 62.2%, respectively, with no significant difference among the three groups. There was no significant difference in the OS rate according to the tumor node metastasis stage among the three groups (P > .05). CONCLUSION: The postoperative complications and prognoses were similar in the different digestive tract reconstruction groups. Billroth I anastomosis is a simple surgical method that can be used for gastrointestinal reconstruction after distal gastrectomy.

4.
Int Immunopharmacol ; 60: 41-49, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29702282

RESUMO

Our previous study showed that wedelolactone, isolated from Ecliptae herba, enhanced osteoblastogenesis but inhibited osteoclastogenesis through Sema3A signaling pathway. This study aims to investigate the role of other semaphorins in wedelolactone-enhanced osteoblastogenesis and -inhibited osteoclastogenesis. Wedelolactone inhibited RANKL-induced Sema4D and Sema7A production, but had no effect on RANKL-reduced Sema6D expression in osteoclastic RAW264.7 cells. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone reversed osteogenic medium(OS)-reduced Sema7A expression and OS-enhanced Sema3E mRNA expression, but no effect on OS-reduced Sema3B mRNA expression. Addition of Sema4D antibody promoted wedelolactone-reduced TRAP activity and bone resorption pit formation. Wedelolactone combined with Sema4D antibody inhibited the formation of Sema4D-Plexin B1 complex. In co-culture of BMSC with RAW264.7 cells, Sema7A antibody, similar with Sema 3A antibody, reversed wedelolactone-enhanced ALP activity and mineralization level, but promoted wedelolactone-inhibited TRAP activity. However, Sema3E and Sema3B antibodies had no effect. Further, wedelolactone enhanced the binding of Sema7A with PlexinC1 and Beta1, but addition of Sema7A antibody partially blocked this binding. Our data demonstrated that wedelolactone inhibited Sema4D production and Sema4D-PlexinB1 complex formation in RAW264.7 cells, thereafter inhibiting osteoclastogenesis. At the same time, wedelolactone enhanced osteoblastogenesis through promoting Sema7A production and Sema7A-PlexinC1-Beta1 complex formation in BMSC.


Assuntos
Cumarínicos/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Ligante RANK , Células RAW 264.7 , Semaforinas/genética , Semaforinas/metabolismo
5.
Dig Dis Sci ; 62(11): 3021-3028, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28258379

RESUMO

BACKGROUND: PVT1 was up-regulated in patients with gastric cancer (GC) and might be as a novel biomarker for predicting GC. However, the exact mechanism of PVT1 exerting functions in GC was still poorly understood. Emerging evidence suggests that long noncoding RNAs may act as endogenous microRNA (miRNA) sponges to bind to miRNAs and regulate their function. AIM: This study aimed to determine the function of PVT1 on miR-152 expression in GC cells. METHODS: The levels of PVT1 and miR-152 were determined in GC tissues by quantitative real-time PCR. The expression of miR-152 was detected in GC cells transfected with PVT1 plasmid or siPVT1. Luciferase assay was performed to verify the regulation of miR-152 to CD151 or FGF2 expression and PVT1 to miR-152 expression. The effects of PVT1 on the expression of CD151 and FGF2 were evaluated by Western blot. RESULTS: PVT1 was up-regulated in GC tissues than that in the matched normal tissues, and mRNA level of miR-152 was decreased. MiR-152 was negatively associated with PVT1 expression in GC tissues. Based on the in silico analysis, we found that PVT1 have three binding sequences for miR-152. Moreover, PVT1 might inhibit the expression of miR-152 and increased the expression of CD151 and FGF2 through regulating miR-152. PVT1 was positively associated with CD151 and FGF2 expression in GC tissues. CONCLUSIONS: PVT1 might act as a "sponge" to inhibit miR-152 in gastric cancer cells. PVT1 is a promising molecular target to improve the diagnosis and therapy of GC.


Assuntos
MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Biologia Computacional , Simulação por Computador , Bases de Dados Genéticas , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Tetraspanina 24/genética , Tetraspanina 24/metabolismo , Transfecção
6.
Pathol Oncol Res ; 21(3): 727-33, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25573590

RESUMO

Studies investigating the association between genetic polymorphism of aldehyde dehydrogenases-2 (ALDH-2) Glu487Lys and colorectal cancer (CRC) risk have reported conflicting results. Given this uncertainty, we carried out a critical analysis of published case-control studies to derive a more precise estimation of this relationship. Published literature from PubMed, EMBASE and China Knowledge Resource Integrated Database were retrieved, and the literature search was updated in June 2014. Eleven studies comprising 6965 subjects were selected (2300 cases and 4665 controls). Overall, our study showed no statistical significance for CRC risk associated with any of the genetic models of ALDH-2 Glu487Lys polymorphism. When studies were stratified for control source, a decreased risk of CRC for participants with Lys/Lys was observed in population based case-control studies [Lys/Lys vs. (Glu/Lys + Glu/Glu): odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38-0.87]. Furthermore, we also confirmed the significant correlation between Glu487Lys polymorphism and the influence on the risk of rectal cancer in males [Glu/Glu vs. (Glu/Lys + Lys/Lys): OR = 1.52, 95%CI = 1.10-2.08]. The combined effects of the two gene polymorphisms [ALDH-2 and alcohol dehydrogenase 1B (ADH-1B)] were also studied. Compared with subjects having ALDH-2 Lys+ with ADH-1B His/His, ORs and 95%CIs for those with ALDH-2 Glu/Glu and ADH-1B His/His was 3.42(0.57-20.38). Similar trends were observed for the other two types of comparisons. Our study supports that ALDH-2 Glu487Lys polymorphism is associated with significant reduced risks of CRC in population-based samples, and of rectal cancer in males.


Assuntos
Aldeído Desidrogenase/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo Genético/genética , Aldeído-Desidrogenase Mitocondrial , Estudos de Casos e Controles , China , Feminino , Humanos , Masculino , Metanálise como Assunto , Prognóstico , Fatores de Risco
7.
Med Oncol ; 31(8): 108, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25005847

RESUMO

Autophagy is a cellular recycling process to enable cell survival in less favorable conditions through degradation of their unnecessary cellular components and utilization of the breakdown components. Autophagy also plays an important role in tumor pathology. In this study, we detected autophagy protein light chain 3 (LC3) and X-linked inhibitor of apoptosis protein (XIAP) in hepatocellular carcinoma (HCC) tissue specimens to assess their role in HCC tumorigenesis and progression. We analyzed expression of LC3, XIAP, and Ki-67 proteins immunohistochemically in surgical specimen of 150 HCC and 136 nontumor hepatic tissues. The levels of LC3 and XIAP proteins were compared between tumor and nontumoral parenchyme. The data showed that LC3 expression was increased in HCC compared with nontumoral parenchyma. LC3 expression was significantly associated with male gender, large tumor size, advanced tumor stages, and worse relapse-free and overall survival (OS). In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. Furthermore, expression of LC3 and XIAP was inversely associated in HCC tissue specimens. In conclusion, increase in autophagic LC3 activity and low XIAP expression could be useful to predict the worse HCC prognosis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Autofagia , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
8.
J Invest Surg ; 27(4): 197-204, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24476004

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Constitutive activation of STAT3 is found in various types of tumors, including HCC. In addition, suppressors of cytokine signaling 3 (SOCS3) signals for negative feedback to STATs, and is found to be inversely correlated with STAT3 expression. However, the exact role of SOCS3 in the tumorigenesis and progression of HCC is not fully understood. In this study we intended to show that SOCS3 inhibition promotes proliferation, migration, and invasion of HCC cells. HepG2, a human HCC cell line, was grown with SOCS3 siRNA or negative control (NC) transfection to assess the involvement of SOCS3 in cell proliferation, migration, and invasion by MTT, migration, and invasion assays, respectively. Western blot analysis was performed to examine the expression of STAT3, SOCS3, c-myc, matrix metalloproteinase (MMP)-2, and MMP-9 after transfection with either SOCS3 or NC siRNAs. A diethylnitrosamine (DEN)-induced HCC mouse model was assessed with or without injection of NSC 74859, a STAT3 inhibitor, to show accompanied changes among the expressions of STAT3, SOCS3, c-myc, MMP-2, and MMP-9. Inhibition of SOCS3 expression promoted the proliferation, migration, and invasion of HepG2 cells and increased the expression of c-myc, MMP-2, and MMP-9. HCC tumors developed in mice by DEN-induction with administration of NSC 74859 resulted in decreased expression of c-myc, MMP-2, and MMP-9, but not SOCS3. Loss of SOCS3 increased tumor growth, migration, and invasion and resulted in accompanied changes in expression of STAT3 and its target oncoproteins.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Ácidos Aminossalicílicos , Animais , Benzenossulfonatos , Movimento Celular , Proliferação de Células , Células Hep G2 , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/metabolismo , Distribuição Aleatória , Proteína 3 Supressora da Sinalização de Citocinas
9.
Tumour Biol ; 35(4): 3431-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24338709

RESUMO

Published data on the relationship between T309G polymorphism in the murine double minute 2 (MDM2) gene and susceptibility of digestive tract cancers (DTC) are inconclusive. Thus, the aim of this study is to determine whether MDM2 T309G polymorphism is associated with the risk of diverse DTC, including esophagus, stomach, liver, bile duct, pancreas, and colorectum cancers. Relevant studies were identified up to October 1, 2013. Crude odds ratio (OR) and 95% confidence interval (CI) were used as a measure of the strength of the association. The pooled result based on all studies showed that there was a statistically significant link between MDM2 T309G polymorphism and DTC susceptibility (T vs. G: OR = 0.82, 95%CI = 0.76-0.88). When stratified by race, significant associations were observed for all genetic models among Asians (especially in Chinese population), but not among Caucasians. Subgroup analyses according to tumor location indicated that the genetic variant was associated with esophageal (OR = 0.88, 95%CI = 0.81-0.96 for T vs. G), hepatocellular (OR = 0.69, 95%CI = 0.57-0.84 for T vs. G) and pancreatic cancer risk but not associated with cholangiocarcinoma or colorectum cancer susceptibility. Meanwhile, the G allele was also suggested to be associated with increased gastric cancer risk (OR = 0.68, 95%CI = 0.54-0.87 for TT + TG vs. GG for intestinal type of gastric cancer and OR = 0.18, 95%CI = 0.06-0.50 for TT vs. GG for Helicobacter pylori infection positive stomach cancer). Our study indicates that the MDM2 T309G polymorphism may be an ethnicity-dependent risk factor for DTC, especially for the upper gastrointestinal tract malignancies.


Assuntos
Neoplasias do Sistema Digestório/etnologia , Neoplasias do Sistema Digestório/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/genética , Neoplasias do Sistema Digestório/etiologia , Genes p53 , Genótipo , Humanos , Fatores de Risco
10.
Neurosci Bull ; 28(2): 165-72, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22466127

RESUMO

OBJECTIVE: Our previous study showed that tumor tissue-derived formaldehyde at low concentrations plays an important role in bone cancer pain through activating transient receptor potential vanilloid subfamily member 1 (TRPV1). The present study further explored whether this tumor tissue-derived endogenous formaldehyde regulates TRPV1 expression in a rat model of bone cancer pain, and if so, what the possible signal pathways are during the development of this type of pain. METHODS: A rat model of bone cancer pain was established by injecting living MRMT-1 tumor cells into the tibia. The formaldehyde levels were determined by high performance liquid chromatography, and the expression of TRPV1 was examined with Western blot and RT-PCR. In primary cultured dorsal root ganglion (DRG) neurons, the expression of TRPV1 was assessed after treatment with 100 µmol/L formaldehyde with or without pre-addition of PD98059 [an inhibitor for extracellular signal-regulated kinase], SB203580 (a p38 inhibitor), SP600125 [an inhibitor for c-Jun N-terminal kinase], BIM [a protein kinase C (PKC) inhibitor] or LY294002 [a phosphatidylinositol 3-kinase (PI3K) inhibitor]. RESULTS: In the rat model of bone cancer pain, formaldehyde concentration increased in blood plasma, bone marrow and the spinal cord. TRPV1 protein expression was also increased in the DRG. In primary cultured DRG neurons, 100 µmol/L formaldehyde significantly increased the TRPV1 expression level. Pre-incubation with PD98059, SB203580, SP600125 or LY294002, but not BIM, inhibited the formaldehyde-induced increase of TRPV1 expression. CONCLUSION: Formaldehyde at a very low concentration up-regulates TRPV1 expression through mitogen-activated protein kinase and PI3K, but not PKC, signaling pathways. These results further support our previous finding that TRPV1 in peripheral afferents plays a role in bone cancer pain.


Assuntos
Neoplasias Ósseas/complicações , Formaldeído/farmacologia , Gânglios Espinais/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Nociceptores/metabolismo , Dor Intratável/induzido quimicamente , Canais de Cátion TRPV/fisiologia , Regulação para Cima/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Formaldeído/sangue , Formaldeído/líquido cefalorraquidiano , Gânglios Espinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/agonistas , Regulação para Cima/fisiologia
11.
Brain Res ; 1427: 65-77, 2012 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22050959

RESUMO

The role of satellite glial cells (SGCs) of sensory ganglia in chronic pain begins to receive interest. The present study aims to investigate the contribution of SGC activation to the development of neuropathic pain. A neuropathic pain model was established by lumbar 5 spinal nerve ligation (SNL), and glial fibrillary acidic protein (GFAP) was used as a marker of SGC activation. It was found that SGCs were activated in the ipsilateral dorsal root ganglia (DRG) increased significantly as early as 4h following SNL, gradually increased to a peak level at day 7, and then stayed at a high level to the end of the experiment at day 56. SGC activation in the SNL group was significantly higher than that in the sham group at days 1, 3 and 7 after operation. Immunofluorescent double labeling showed that the activated SGCs encircled large, medium-sized and small neurons. The SGCs surrounded the small and medium-sized neurons were preferentially activated in the early phase, but shifted to large diameter neurons as time went on. Continuous infusion of fluorocitrate, a glial metabolism inhibitor, to the affected DRG via mini-osmotic pump for 7d significantly alleviated mechanical allodynia at day 7. These results suggest that SGCs in the DRG were activated after SNL. SGC activation contributed to the early maintenance of neuropathic pain.


Assuntos
Gânglios Espinais/patologia , Gliose/patologia , Doenças do Sistema Nervoso Periférico/patologia , Células Satélites Perineuronais/patologia , Animais , Dor Crônica , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Masculino , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Células Satélites Perineuronais/efeitos dos fármacos , Células Satélites Perineuronais/fisiologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia
12.
Zhonghua Yi Xue Za Zhi ; 92(48): 3426-8, 2012 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-23327705

RESUMO

OBJECTIVE: To explore the clinical characteristic and therapeutic strategies of acute appendicitis after radical gastrectomy for gastric carcinoma. METHODS: The clinical data of 31 patients with acute appendicitis after radical gastrectomy for gastric carcinoma from January 2006 to January 2012 was analyzed retrospectively. The profiles of previous operations, symptoms, physical signs, disease duration, progression time, examination results, peri-operative complications, results of bacterial culture and use of antibiotics were used to evaluate the clinical characteristics and therapeutic strategies. RESULTS: There were 19 males and 12 females with a mean age of (61 ± 4) years. Gastric cancer postoperative acute appendicitis lacked typical symptoms. The presenting symptoms were persistent and progressive severe right lower abdominal pains (n = 31, 100.0%), associated, with fever (n = 27, 87.1%) nausea or vomiting (n = 11, 35.5%), abdominal distension (n = 9, 29.0%), intestinal obstruction (n = 21, 67.7%) and abdominal purulent exudate (n = 31, 100.0%). The average onset time from abdominal pain to peritonitis was (15 ± 4) hours. Perforated appendix occurred in 16 cases (51.6%). Seven patients had no increase of the total number of WBC or percentage of neutrophils (22.6%). Exploratory laparotomy was performed in 17 cases, and the rate of delayed diagnosis was 54.8%. And 31 patients were cured by surgery and anti-infection treatment. There was no intraoperative death. CONCLUSIONS: Because of rapidly spreading abdominal infection, peritonitis occurs early with a high incidence rate. Early diagnosis, early operation and rational use of antibiotics are the most important therapeutic modalities of acute postoperative appendicitis in patients with gastric cancer.


Assuntos
Apendicite/diagnóstico , Apendicite/etiologia , Gastrectomia/efeitos adversos , Complicações Pós-Operatórias , Neoplasias Gástricas/cirurgia , Doença Aguda , Idoso , Apendicite/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
BMC Cancer ; 11: 506, 2011 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-22136659

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. METHODS: Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. RESULTS: Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. CONCLUSION: Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Monócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Ácidos Aminossalicílicos/farmacologia , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Benzenossulfonatos/farmacologia , Carcinógenos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina , Modelos Animais de Doenças , Progressão da Doença , Humanos , Interleucina-6/farmacologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Monócitos/efeitos dos fármacos , RNA Ribossômico 18S/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores
14.
Exp Ther Med ; 2(4): 647-653, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22977555

RESUMO

Altered expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and suppressor of cytokine signaling 3 (SOCS3) has been implicated in various types of human cancers. However, the clinical role of pSTAT3 and SOCS3 in hepatocellular carcinoma (HCC) is not well established. Immunohistochemical analysis of pSTAT3, SOCS3, Ki67 and VEGF expression was performed on tissue microarrays from 138 HCC patients. The expression of STAT3 mRNA was further detected by in situ hybridization. The association of pSTAT3 and SOCS3 expression with clinicopathological factors and patient survival was analyzed. Altered expression of pSTAT3 and SOCS3 was observed in HCC specimens, compared to adjacent non-tumor tissue. Increased expression of pSTAT3 was correlated with large tumor size, higher clinical stage, Ki67 and VEGF expression, as well as poor patient survival. Decreased expression of SOCS3 was correlated with the expression of Ki67, VEGF and pSTAT3, and poor patient survival. Moreover, the expression of pSTAT3 was conversely correlated with SOCS3 expression in HCC. Our results indicate that deregulated expression of pSTAT3 and SOCS3 may play roles in the development and progression of HCC. PSTAT3 and SOCS3 should be further evaluated as potential novel biomarkers for HCC prognosis.

15.
Hepatol Res ; 29(1): 13-17, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15135341

RESUMO

Objective: Spontaneous rupture of hepatocellular carcinoma (HCC) is common in Asia and Africa with unclear mechanism. In our previous study, we found that the vascular injury was related to the HCC rupture. In this study, the structure of elastin around the small artery was deeply investigated to confirm our previous study. Methods: Immunohistochemical technique and transmission electron microscopy were used to study 23 specimens from ruptured HCC and 30 cases with nonruptured HCC. Results: The layer of elastin around the vascular wall was significant thicker in patients with ruptured HCC than that in nonruptured HCC. The proliferation of elastin, abnormal distribution of neutrophil elastase and degradation of collagen fibril were predominantly present in the specimens from ruptured HCC. The phenomenon that the infiltrated neutrophils from bloodstream into the vascular wall, which caused the vascular injury, can be found in specimens from ruptured HCC. The vascular injury mainly occurred in small artery. Since the damaged vessels could become stiff and weak, which would be more prone to splitting and result in hemorrhage in patients with ruptured HCC, we postulated that the vascular injury, especially the inelastic small artery, may relate the ruptured HCC. Conclusion: The vascular injury in small artery might relate to ruptured HCC.

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